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COLUMBIA    UNIVERSITY 

EDWARD    G.    JANEWAY 

MEMORIAL    LIBRARY 


THE     PITUITARY 

A  STUDY  OF  THE  MORPHOLOGY, 
PHYSIOLOGY,  PATHOLOGY,  AND 
SURGICAL  TREATMENT  OF  THE 
PITUITARY,  TOGETHER  WITH  AN 
ACCOUNT  OF  THE  THERAPEU- 
TICAL USES  OF  THE  EXTRACTS 
MADE        FROM        THIS        ORGAN 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/pituitarystudyofOObell 


THE     PITUITARY 


A  STUDY  OF  THE  MORPHOLOGY,  PHYSI- 
OLOGY, PATHOLOGY,  AND  SURGICAL 
TREATMENT  OF  THE  PITUITARY, 
TOGETHER  WITH  AN  ACCOUNT  OF 
THE  THERAPEUTICAL  USES  OF  THE 
EXTRACTS    MADE     FROM    THIS     ORGAN 


BY 

W.    BLAIR    BELL 


NEW  YORK 
WILLIAM     WOOD    &    COMPANY 

MDCCGCXIX 


-A-fc 


5  41 

GcrX>>     \ 


PKINTED  IN  GKEAT  BUtTAfN 


TO 

MY    FRIEND 

J.    ARTHUR  SMITH 


PREFACE 

In  this  monograph  an  attempt  has  been  made  to  describe  and 
discuss  within  a  reasonable  compass  our  present  knowledge  with 
regard  to  the  Pituitary  Body,  in  the  belief  that  a  more  or  less 
complete  summary  of  the  subject  is  needed  by  the  clinician, 
if  not  by  the  morphologist  and  physiologist,  owing  to  the  com- 
manding position  this  organ  now  occupies  in  Medicine,  Surgery, 
and  Gynaecology,  as  well  as  in  the  other  specialities.  Descriptions 
of  the  Pituitary  are  to  be  found  in  various  monographs,  such  as 
those  of  Thaon,  Fischer,  and  dishing,  and  in  the  works  on  the 
internal  secretions  of  Biedl,  Vincent  and  others  ;  but  in  one  aspect 
or  another  these  accounts  appear  to  lack  the  completeness,  manner 
of  presentation,  or  point  of  view  that  is  required  by  the  general 
reader,  however  well  they  fulfil  special  requirements. 

Our  own  experimental  work — commenced  in  1906-  was 
primarily  undertaken  in  order  to  elucidate  the  relationship  of 
the  Pituitary  to  the  female  genital  functions,  and  to  determine 
the  physiological  and  therapeutical  importance  of  extracts  made 
from  this  organ;  but  we  were  led  in  our  investigations  further 
afield,  for  it  was  difficult  to  study  comprehensively  such  special 
aspects  as  those  mentioned  without  first  obtaining  an  intimate 
knowledge  of  the  morphology,  and,  so  Jar  as  possible,  of  the 
pathology  of  the  organ  in  question.  Thus  it  came  about  that  a 
considerable  amount  of  material  and  information  was  collected 
from  the  work  of  others,  and  also  as  the  result  of  our  own  observa- 
tions. Our  researches  have  been  concerned  with  the  histological 
anatomy  from  developmental,  physiological  and  comparative 
points  of  view;  with  the  physiological  actions  of  the  extracts, 
the  interrelationships  between  the  Pituitary  and  other  organs  of 
internal  secretion,  the  effects  of  partial  and  complete  removals, 
the  results  of  experimentally  produced  infections,  the  general 
pathology,    and    with    the    therapeutical    uses    of    extracts    of    the 


viii  PREFACE 

Pituitary.     It  is  the  information  and  material  so  obtained  that 
form  the  subject-matter  of  this  volume. 

It  would  be  impossible,  of  course,  completely  to  discuss  all 
the  work  that  has  been  done  in  regard  to  the  Pituitary — to  do 
so  would  mean  a  compilation  of  many  volumes  containing  much 
confirmatory  and  contradictory  evidence.  Only  the  more  essential 
particulars,  therefore,  have  been  given  ;  for  at  the  present  time 
a  critical  study  of  the  accuracy  of  our  acquired  information  and 
an  attempt  to  correlate  our  knowledge  is  probably  more  needed 
than  a  mere  string  of  statements.  For  the  same  reason  a  com- 
prehensive bibliography  of  the  subject  has  not  been  attempted, 
but  numerous  references  to  statements  quoted  and  investigations 
mentioned  are  given. 

In  these  circumstances  it  is  jiossible  that  valuable  work  of 
others  has  escaped  attention,  and  that  our  own  less  important 
investigations  have  been  given  undue  prominence.  If  so,  it  may 
be  pointed  out  that  this  book  is  not  intended  to  be  a  mere  com- 
pilation, but,  rather,  the  presentation  of  an  attempt  to  study  the 
Pituitary  from  every  point  of  view. 

Some  of  the  original  work  contained  in  the  following  pages  has 
been  published  previously  ;  and  it  includes  that  for  which  the 
author  was  awarded  the  John  Hunter  Medal  and  the  Triennial 
Prize  by  the  Council  of  the  Royal  College  of  Surgeons,  England, 
and  the  Astley  Cooper  Prize,  as  well  as  the  substance  of  a  Hunterian 
Lecture  delivered  at  the  Royal  College  of  Surgeons. 

In  addition  to  my  obligation  to  Mr.  Arthur  Smith,  who  has 
defrayed  the  laboratory  expenses  in  connexion  with  my  researches, 
and  to  whom  this  work  is  inscribed,  I  am  indebted  to  my  colleagues 
Professor  J.  A.  McDonald  and  Professor  E.  E.  Glynn  for  laboratory 
facilities.  Miss  Miriam  Alderson  has  given  me  much  valuable 
assistance,  especially  in  regard  to  the  references  and  in  the  com- 
pilation of  the  index.  My  laboratory  assistant — now  Private 
Walter  Plevin,  R.A.M.C— has  drawn  many  of  the  illustrations 
other  than  the  photographs.  Private  Fred  Holliday,  also,  has 
been  responsible  for  some  of  the  pictures.  Owing  to  the  difficulty 
of  securing  artistic  assistance  after  they  had  left,  a  number  of 
photomicrographs  have  been  reproduced  ;  and  at  the  last  moment 
Miss  E.  M.  Wright  kindly  drew  a  few  illustrations.  All  the  photo- 
graphs and  drawings,  other  than  those  indicated,  have  been  made 
from  my  own  material. 


PREFACE  ix 

As  this  work  has  been  produced  at  a  time  of  great  stress  and 
difficulty,  some  allowance  must  be  made  for  imperfections  that 
may  be  found  in  regard  to  publication  and  authorship.  I  must, 
however,  thank  Mr.  W.  A.  Clowes  of  Messrs.  William  Clowes  and 
Sons  for  the  personal  interest  he  has  taken  in  the  printing  of 
the  book,  and  Dr.  Hubert  Armstrong  for  reading  the  proofs. 


W.    B.    B. 


38,  Rodney  Street, 
Liverpool, 

November,  1918. 


CONTENTS 


Preface    . 
Introduction 


PAGE 

vii 


PART  I 


THE    MORPHOLOGY    OF   THE    PITUITARY 


§   i.  Development  of  the  Pituitary 

§  ii.    AxATOMY   OF   THE   PITUITARY       . 

Macroscopical  anatomy 
Histological  anatomy   .    -      . 
§  iii.  Comparative  Anatomy  of  the  Pituitary 
Cyclostomata 
Pisces  . 
Amphibia 
Reptilia 
Aves 
Mammalia 


3 

14 
14 
28 
40 
4ft 
13 
4!< 

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52 
55 


PART  II 

THE   PHYSIOLOGY   OF   THE   PITUITABT 

§  i.  Phtsiologicai  In\  i  stig  ltions 

Histological  Observations 

Chemical  examination  of  pituitary  tissues  and  body-fluids 

Chemistry  of  pituitary  . 

[nfundibulin  and  the  cerebrospinal  fluid 
Injection,  ingestion  and  absorption  experiments 

Immediate  results  of  injections  and  absorption  of  extract* 

Late  results  of  injection  and  ingestion  of  extracts 


82 
82 
KM 
101 
102 
1 | 16 
105 
122 


xii  CONTENTS 

PAGE 

§  ii.  Pathophysiological  Investigations 126 

Operations  on  the  pituitary .         ........  126 

Destruction  of  the  pituitary           .         .         .         .         .         .         .  1  •_'<'» 

Removal  of  the  pituitary       ........  127 

Extirpation  combined  with  implantation  of  grafts         .         .         .  170 

Stimulation  of  the  pituitary  in  situ        ......  17<» 

Interrelations  between  the  pituitary  and  the  other  hormonopoietic 

organs 178 

Supplementation  with  pituitary  extracts        .....  180 

Removal  of  the  other  hormonopoietic  organs        ....  182 
Discussion  of  results  of  removal  of  the  various  hormonopoietic 

organs 204 

Effects  of  inoculations  with  bacteria     .......  207 

The  interpretation   of  pathological   processes    affecting   the   normal 

physiology 211 

§  iii.  Comparative  Physiology 214 


PART  III 

DISORDERS   ASSOCIATED   WITH   THE   PITUITARY   AND 
THEIR   TREATMENT 

§  i.  Primary  lesions  of  the  Pituitary 218 

Hyperpituitarism  ..........  218 

Acromegaly  . 219 

Hypopituitarism 238 

Polyglandular  affections  in  primary  hypophysial  lesions      .         .         .  248 
Primary  lesions   of  the   pituitary  producing    symptoms    neither   of 

excessive  nor  of  diminished  secretion        ......  253 

§  ii.  Secondary  lesions  of  the  Pituitary .  259 

Neighbouring  pathological  conditions  ......  259 

Diseases  of  the  other  hormonopoietic  organs 262 

Metastases 269 

Infections 270 

Toxaemias  of  pregnancy       .         .         .         .         .         .         .         .         .  272 

§  iii.  General  consideration  of  the  Pathology  of  the  Pituitary  .         .  i'7'i 

§  iv.  Treatment  of  Pituitary  lesions 280 

Medical  treatment  of  phenomena  due  to  pituitary  lesions  .  .         .  280 

Surgical  treatment  of  pituitary  lesions  ......  282 

Surgical  anatomy  ..........  282 

Indications  for  operation 286 

Selection  of  the  route  of  approach 286 

Preparation  of  the  patient 287 

Intracranial  methods     .........  287 

Extracranial  methods    .........  291 

Results  of  operations 299 


CONTENTS  xiii 
PART  IV 

THE    THERAPEUTICAL   USES   OF   PITUITARY   EXTRACTS 

PAGK 

§  i.    G-EXKKW.    CONSIDERATIONS 301 

Methods  of  manufacture       .         .         .         .         .         .         .         .  302 

Methods  of  administration     ........  303 

General  indications  for  administration          .....  304 

General  contraindications      ........  305 

§  ii.  Effects  produced  by  Pituitary  extb  lots    ......  306 

Pressor  effects  of  infundibulin      ........  300 

Circulatory  system 306 

Uterus 310 

Alimentary  tract  .         .         . .">•_'  1 

Urinary  system .".L'l 

Mammary  glands  ..........  322 

Spleen 323 

Substitution  and  supplementary  effects  of  pituitary  extracts       .        .  32 1 

Antagonistic  and  metabolic  effects  of  pituitary  extracts       .         .         .  327 

Ixdex 331 


ILLUSTRATIONS 

PART  I 

PACING   PAGE 

Plate       1.     Section  of  the  normal  human  pars  anterior    .....       30 
Plate       2.      Section   of  the   normal  human  pars  anterior,   showing  basophil 

colloid .;] 


Figure 

1. 

figure 

2. 

Figure 

3. 

Figure 

4. 

Figure 

5. 

Figure 

6. 

Figure 

7. 

Figure 

8. 

Figure 

9. 

Figure 

10. 

Figure 

11. 

Figure 

12. 

Diagram  of  the  earliest  stage  of  development 
Diagram  of  the  second  stage  of  development 
Section  of  head-end  of  human  foetus  4  mm.  in  length    . 
Section  of  stomodeum  and  encephalon  of  human  foetus  9  mm.  in 
length  .......... 

Diagram  of  the  development  of  the  infundibular  process 
Section  of  pituitary  region  of  human  foetus  10  nun.  in  length 
Section  of  pituitary  region  of  human  foetus  16  mm.  in  length 
Section  of  pituitary  region  of  human  ftetus  16  mm.  in  length 
Diagrammatic   representations    of   pituitary   in  a  human    fcetu 
16  mm.  in  length         ........ 

Section  of  the  pituitary  region  of  human  foetus  ?•">  mm.  in  length 
Median  horizontal  section  of  the  adult  human  pituitary 
Base  of  human  skull  showing  sella  turcica    .... 

Figure  13  a.  Radiograph  of  normal  human  sella  turcica  .... 

b.  Radiograph  of  normal  human  sella  turcica    .... 

Figure  11.     Macroscopical    sections    of    pituitary    region    in    human   adults, 

showing  sphenoidal  cells  in  relation  to  sella-  turcica1 
Figure  15.      Internal  circulation  of  pituitary  of  cat  .  .... 

Figure  16.      Diagram  of  the  external  circulation  of  human  pituitary 
Figure  1".     Section  of  human  pars  anterior,  showing  blood-sinuses 
Figure  IS.      Section  of  human  pars  anterior,  showing  acini  with  secretion 
Figure  19.     Section  of  human  par-  anterior,  showing  basophil  cells 
Figure  20.     Section  of  human  pars  anterior,  showing  sympathetic  fibres 

Figure  21.     Section  of  human  pars  intermedia 

Figure  22.     Neuroglial  cells  and  fibres  in  pars  uervosa  of  cat  . 

Figure  23\     Pituitary  of  the  lamprey 

Figure  24.      Pituitary  of  the  skate  

Figure  25.     Section  of  distal  epithelial  portion  ..t  pituitary  of  the  akate  . 
Figure  26.      Pituitary  of  the  cod 


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6 

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in 


XVI 


ILLUSTRATIONS 


Figure  27.  Pituitary  of  the  eel         .... 

Figure  28.  Pituitary  of  the  frog       .... 

Figure  29.  Pituitary  of  the  salamander   . 

Figure  30.  Pituitary  of  the  lizard    .... 

Figure  31.  Pituitary  of  the  tortoise 

Figure  32.  Pituitary  of  the  fowl      .... 

Figure  33.  Pituitary  of  ornithorhynchus 

Figure  34.  Section  of  pars  anterior  of  ornithorhynchus 

Figure  35.  Section  of  pars  posterior  of  ornithorhynchus 

Figure  36.  Section  of  pars  nervosa  of  ornithorhynchus 

Figure  37-  Pituitary  of  the  opossum 

Figure  38.  Section  of  pituitary  of  the  opossum 

Figure  39.  Pituitary  of  the  ox         .... 

Figure  40.  Section  of  the  pars  nervosa  of  the  ox     . 

Figure  41.  Pituitary  of  the  sheep    .... 

Figure  42.  Section  of  distal  epithelial  portion  of  pituitar 

Figure  43.  Section  of  distal  epithelial  portion  of  pituitar 

Figure  44.  Pituitary  of  the  pig         .... 

Figure  45.  Pituitary  of  the  guinea-pig    . 

Figure  40.  Pituitary  of  the  rabbit  .... 

Figure  47.  Pituitary  of  the  cat         .... 

Figure  48.  Section  of  pituitary  of  the  cat 

Figure  49.  Section  of  pars  intermedia  of  the  cat     . 

Figure  50.  Section  of  pars  intermedia  of  the  cat     . 

Figure  51.  Pituitary  of  the  dog        .... 

Figure  52.  Section  of  pars  intermedia  of  the  dog     . 

Figure  53.  Section  of  pars  intermedia  of  the  dog    . 

Figure  54.  Pituitary  of  the  hedge-hog     . 

Figure  55.  Section  of  pars  anterior  of  the  hedge-hog 

Figure  56.  Pituitary  of  the  lemur   .... 

Figure  57.  Section  of  pars  posterior  of  the  lemur    . 

Figure  58.  Section  of  pars  anterior  of  the  lemur 

Figure  59.  Pituitary  of  the  monkey 

Figure  60.  Pituitary  of  Man    ..... 


y  of  sheep 


y  of 


sheep 


47 
49 
50 
50 
51 
53 
55 
56 
57 
57 
.">!', 
59 
61 
62 
(52 
63 
64 
64 
65 
0.1 
66 
67 
68 
68 
69 
70 
71 
72 
72 
73 
74 
75 
75 
76 


PART  II 


FACING   PAGE 

of   cat    after    thyroidectomy    during 


Plate      3.     Section    of    pars    anterior 

pregnancy  ........... 

Plate  4.  Section  of  pars  anterior  of  non-pregnant  cat  after  thyroidectomy 
Plate  5.  Section  of  pars  anterior  of  non-pregnant  cat  after  oophorectomy 
Plate  6.  Section  of  pars  intermedia  of  non-pregnant  cat  after  oophorectomy 
Plate      7.     Section  of  pars  anterior  of  non-pregnant  cat  after  removal  of 

suprarenals  .......... 


186 
187 
192 
193 

199 


ILLUSTRATIONS  xvii 


PAGE 


Figure  61.     Section  of  pars  anterior  of  pregnant  rabbit 84 

Figure  62.     Section  of  pars  anterior  of  pregnant  rabbit 84 

Figure  63.     Section  of  pars  anterior  of  pregnant  guinea-pig     ....       86 

Figure  64.     Section  of  pars  anterior  of  pregnant  woman 86 

Figure  65  a.  Section  of  pituitary  of  non-hibernating  hedge-hog         ...       88 
b.  Section  of  pituitary  of  hibernating  hedge-hog       ....      88 

Figure  66  a.  Section  of  pars  anterior  of  laying  hen  90 

I?.  Section  of  pars  anterior  of  non-laying  hen     .         .         .         .         .90 

Figure  67.     Section  of'human  pars  anterior,  showing  colloid   ....       93 

Figure  68.     Section  of  human  pars  anterior,  showing  lipoids    ....       !»4 

Figure  69.     Section  of  pars  nervosa  of  cat,  showing  granular  bodies         .         .       I'll 
Figure  7".     Kymograph-tracing    showing    effect    of   infundibulin    on    blood- 
pressure  and  uterine  contractions        ......     107 

Figure  71.     Kymograph-tracing  showing  effect  of  infundibulin  on  contractions 

of  distended  bladder  .         .....         Facing  page     ll'» 

Figure  72.     Kymograph-tracing  showing  effect  of  infundibulin  on  contractions 

in  the  empty  bladder  .....         Facingpage     110 

Figure  73.      Uterine  cannula     .         .         .         .         .         .         .         .         .         .Hi' 

Figure  74.      Kymograph-tracing  showing  defecation  caused  by  infundibulin     .     113 
Figure  75.      Kymograph-tracing  showing  effect  of  infundibulin   on   intestine 

Facing  page     114 
Figure  76.     Kymograph-tracing  showing  effect  of  infundibulin    on  intestine 

Facing  page     114 
Figure  77.     Kymograph-tracing   showing   effect  of  infundibulin    on   rate    of 

milk-expulsion    .         .         .         .         .         .         .         .         .         .llti 

Figure  78.      Kymograph-tracing    showing    effect    of  infundibulin   on   rate   of 

milk-expulsion    .         .         .         .         .         .         .         .         .         .llti 

Figure  79.     Section  of  adjacent  mammae,  one  of  which  had  been  emptied  by 

infundibulin         .         .         .         .         .         .         .         .         .         .117 

Figure  80.     Sections  of  mammae  showing  filling  of  alveoli  after  injection  of 

infundibulin         .  .  .  .  .  .  .  .  .  .118 

Figure  81.     Apparatus  for  administration  of  intra-tracheal  ether      .         .        .     I"'11 
Figure  82.     View  of  operating-table  .         .         .         .         .         .         •         .132 

Figure  83.     View  of  operating-table  .         .         .         .        •         •         •         .132 

Figure  84.      Hitch"-  bead  showing  line  of  incision  for  removal  of  pituitary        .     L33 
Figure  85.     Field  of  operation  after  bilateral  opening  has  been  made       .        .     L34 
Figure  86.     Radiograph  of  bitch's  head  after  operation     .....     135 

Figure  87.     Soft  metal  spoon-shaped  retractor  ......     L3o 

Figure  88.     Hooked-knife  for  incising  dura      .......     Ki<> 

Figure  89.     Field  of  operation  with  pituitary  exposed 137 

Finnic  90.     Angular  forceps     ...•■•••••     138 
Figure  91.     Aural  forceps         .....•••■•     138 

Figure  92.     Chisel-hook '-'is 

Figure  93.     Watson-Cheyne's  dissectoi 139 

Figure  94  \.  Bitch  before  control  operation       ....-••     14'-' 

B.  Bitch  after  control  operation  .         ■         •         •         •         •         .142 

Figure  95.     Section  showing  anterior  and  posterior  lobes  removed  al  operation     I  13 

Figure  96.     Section  of  base  of  brain  at  site  of  removal  of  pituitary  .        .        .     143 


XV111 


ILLUSTRATIONS 


Figure  97.  Section  of  pars  anterior  removed  by  operation 
Figure  98.  Section  of  pars  anterior  removed  by  operation 
Figure  99  a.     Bitcb  before  partial  removal  of  pars  anterior 

B.      Bitch  after  partial  removal  of  pars  anterior 
Figure  100.     Section  of  pars  anterior  removed  by  operation 


Page 
145 
148 
149 
149 
150 


Figure  10* 


Fit 


I'i 


108 


Figure  101  a.     Section  of  uterus  of  bitcb  before  partial  removal  of  pars  anterior     151 

B.     Section  of  uterus  of  bitcb  after  partial  removal  of  pars  anterior     151 

Figure  102.     Section  of  pars  posterior  removed  by  operation    ....     152 

Figure  103.     Section  of  base  of  brain  at  site  of  removal  of  pars  posterior  .     152 

Figure  104  a.     Bitch  before  removal  of  pars  posterior      .....     154 

B.     Bitch  after  removal  of  pars  posterior         .....     154 

Figure  105  a.      Section  of  uterus  of  bitch  before  removal  of  pars  posterior        .     155 
B.     Section  of  uterus  of  bitch  after  removal  of  pars  posterior  .     155 

Figure  10(5.     Section  showing  partial  removal  at  operation  of  pars  anterior  and 

pars  posterior   ..........     157 

Bitch  before  compression  of  infundibular  stalk  .         .         .     160 

Bitch  after  compression  of  infundibular  stalk    ....     100 

Bitch  before  separation  of  infundibular  stalk     ....     161 

Bitch  after  separation  of  infundibular  stalk       ....     161 

jure  109.     Bitch   opened  to   show   fat-deposit  and  atrophied    uterus   after 

separation  of  infundibular  stalk         ......     162 

Figure  110  A.     Section  of  uterus  before  separation  of  infundibular  stalk  .         .     163 
B.     Section  of  uterus  after  separation  of  infundibular  stalk      .         .     163 
Section  of  the  pars  anterior  after  compression  of  infundibular 

stalk 164 

Bitch  after  insertion  of  an  artificial  tumour  in  neighbourhood  of 
pituitary   ...........     17-"> 

Radiograph  showing  artificial  tumour  in  situ        ....     174 

Section  showing  cyst  in  pars  anterior  caused  by  artificial  tumour     175 
Radiograph  showing  artificial  tumour  in  situ        ....     176 

Section  showing  displacement  of  the  lobes  of  the  pituitary  by  an 
artificial  tumour        .........     177 

Section  of  pars  anterior  of  guinea-pig  after  injections  of  extract 
of  pars  anterior  .........     181 

Section  of  suprarenal  cortex  after  injections  of  extract  of  pars 
anterior     ...........     181 

Section  of  pars  anterior  of  pregnant  cat  after  thyroparatbyroid- 
ectomy      ...........     184 

Figure  120.     Section  of  pars  nervosa  of  pregnant  cat  after  thyroparathyroid - 

ectomy      ...........     184 

Section  of  pars  anterior  of  puerperal  cat  after  thyroidectomy       .     185 
Section  of  pars  intermedia  of  puerperal  cat  after  thyroidectomy     186 
Section    of    pars  anterior    of   cat    after   thyroidectomy    during 
pregnancy  ..........     186 

Section  of  pars  intermedia  of  non-pregnant  cat  after  thyroid- 
ectomy        188 

Section  of  thyroid  of  dog  after  removal  of  pituitary     .         .         .     191 
Section  of  thyroid  of  dog  after  compression  of  infundibular  stalk     191 


Figure  111. 

Figure  112. 

Figure  113. 
Figure  114. 
Figure  115. 
Figure  116. 


Fit 


I'i 


m 


118. 


Figure  111). 


Figure  121. 
Figure  122. 
Figure  123. 

Figure  124. 

Figure  125. 

Figure  126. 


ILLUSTRATIONS  xix 

PAGE 

Figure  127.     Section  of  pars  anterior  of  non-pregnant  cat  after  oophorectomy  193 
Figure  128.      Section  of  reticulated  portion  of  pars  intermedia  after  oophor- 
ectomy     ...........  194 

Figure  120.     Section  of  pars  posterior  of  non-pregnant  cat  after  oophorectomy  194 
Figure  130.     Sections   of  ovaries  of  bitch   before   (a)  and  after  (is)   partial 

removal  of  pars  anterior    ........  196 

Figure  131  a.     Section  of  ovary  of  bitch  before  separation  of  infundibular  stalk  107 

B.     Section  of  ovary  of  bitch  after  separation  of  infundibular  stalk  1 1)7 
Figure  132.     Sections  of  ovaries  of  bitch  before  (a)  and  after  («)  removal  of 

pars  posterior    ..........  198 

Figure  133.     Section  of  pars  posterior  of  cat  after  removal  of  suprarenals        .  200 

Figure  134.      Section  of  pars  nervosa  of  cat  after  removal  of  suprarenal-           .  200 

Figure  135.     Section  of  pars  anterior  of  cat  after  removal  of  suprarenals          .  201 

Figure  136.     Section  of  pars  posterior  of  cat  after  removal  of  suprarenals         .  201 

Figure  137.     Section  of  thymus  of  the  bitch      .......  204 

Figure  138.     Section  of  pars  anterior  of  normal  guinea-pig      ....  208 

Figure  139.     Section   of  the   pars  anterior  of  guinea-pig  after  injections   of 

emulsion  of  colon  bacillus          .......  L'Oii 

Figure  140.     Section  of  the  pars   anterior  of  guinea-pig  after   injections   of 

emulsion  of  staphylococcus        .......  20!t 


PART  III 

Figure  141.      Radiograph  of  sella  turcica  in  case  of  acromegaly         .         .         .  221 

Figure  142.      Base  of  skull  in  case  of  acromegaly      ......  222 

Figure  143.     Radiograph  of  sella  turcica  in  case  of  acromegaly        .         .         .  l'l':'. 

Figure  144.     Radiograph  of  sella  turcica  in  case  of  acromegaly        .        .        .  l'l'.'! 

Figure  145.     Acromegaly  in  a  woman       .         .         .         .         .         .         .         .  l'2  I 

Figure  14(5.      Radiograph    of    hand    of    woman    suffering    with    acromegaly 

Facing  /»i</r  224 

Figure  147.     Acromegaly  in  woman,  showing  prognathism      ....  l'2.~> 

Figure  148.     Acromegaly  in  woman,  showing  separation  of  the  teeth      .         .  l'l'."> 

Figure  149.      Fields  of  vision  in  case  of  acromegaly           .....  L'27 

Figure  150.     Fields  of  vision  in  case  of  acromegaly           .....  228 

Figure  151.      Median   sections  of  normal   pituitary  and    pituitary  from  case  of 

acromegaly        .         .         .         .         .         .         .         .         .  .231 

Figure  152.     Section  of  pars  anterior  removed  from  case  of  acromegaly  .         .  233 

Figure  153.     Case  of  general  infantilism  due  to  pituitary  insufficiency     .         .  237 

Figure  154.     Radiograph  of  sella  turcica  in  case  of  general  infantilism    .         .  238 

Figure  155.     Case  of  dystrophia  adiposogenitalis        ......  239 

Figure  156.     Radiograph    of  sella    turcica    in    case   of  underdevelopraenl   of 

pituitary 240 

Figure  157.     Case  of  dystrophia  adiposogenitalis        ■        •        ■        ■        •         .  I'll 

Figure  158.     Fields  of  vision  in  case  of  dystrophia  adiposogenitalis    .        .        .  242 
Figure  159.     Left  fields  of  vision  in  case  of  dystrophia  adiposogenitalis,  showing 

progression  towards  blindness  ....... 


XX 


ILLUSTRATIONS 


Figure  1(50.  Radiograph  of  the  sella  turcica  in  case  of  dystrophia   advposo- 
genitalis     ........... 

Figure  161.  Section    of  the  pars  anterior    from  case  of   dystrophia    adiposo- 
genital    ........... 

Figure  162.  Case  of  Addison^s  disease  and  acromegaly  in  a  man 

Figure  163.  Section  of  pars  anterior  of  young  woman,  showing  a  chromophobe 
tumour      ........... 

Figure  164.  Section  of  the  suprarenal  of  young  woman,  showing  hyperplasia 

Figure  165.  Radiograph  of  the  sella  turcica  in  case  of  loss  of  sight 

Figure  166.  Diagram  showing  the  optic  nerves  and  tracts        .         .         .         . 

Figure  167.  Cholesteatoma  in  neighbourhood  of  pituitary       .         .         .         . 

Figure  168.  Erosion  of  posterior  clinoid  process  l>y  cholesteatoma  . 

Figure  169.  Section  of  pars  anterior  of  cretin           ...... 

Figure  170.      Section  of  pituitary  of  cretin 

Figure  171.  Section  of  pars  anterior  in  case  of  parenchymatous  goitre   . 

Figure  17-.  Section  of  pituitary  in  case  of  parenchymatous  goitre 

Figure  173.  Section  of  pars  anterior  in  case  of  exophthalmic  goitre 

Figure  174.  Section  of  pars  anterior  in  case  of  eclampsia         .         .         .         . 

Figure  175.  Section  of  pituitary  in  case  of  eclampsia       .         .         .          .         . 

Figure  176.  Section  of  pars  posterior  in  case  of  eclampsia       .         .         .         . 

Figure  177.  Section  of  pars  anterior  in  case  of  cortical  necrosis  of  kidneys     . 

Figure  178.  Section  of  pars  intermedia  in  case  of  cortical  necrosis  of  kidneys 

Figure  179.  Diagrams  showing  incisions  for  various  operative  procedures  that 
have  been  adopted     ........ 

Figure  180.  Sectional  measurements  in  relation  to  sella  turcica 

Figure  181.  Directions  of  approach  in  intracranial  operations 

Figure  182.  Frazier's  orbitofrontal  method  of  approach . 

Figure  183.  Directions  of  approach  in  extracranial  operations 

Figure  184.  First  stage  of  submucous  inferior  nasal  operation 

Figure  185.  Second  stage  of  submucous  inferior  nasal  operation 

Figure  186.  Third  and  fourth  stages  of  submucous  inferior  nasal  operation 


243 

247 

250 

251 
252 
254 
256 
260 
261 
263 
263 
265 
265 
266 
273 
273 
274 
274 
275 

283 

285 
287 
290 
292 
295 
296 
297 


PART  IV 


Figure  187.     Kymograph-tracing  showing  effect  of  infundibulin  in  primary 

uterine  inertia  ..........     314 

Figure  188.     Kymograph-tracing  showing  effect  of  infundibulin  in  secondary 

uterine  inertia  ..........     314 

Figure  189.     Chart  showing  effect  of  infundibulin  in  secondary  uterine  inertia     316 

Figure  190.      Kymograph-tracing    showing  tetanic  contractions  followed   by 

rhythmical  contractions,  after  an  injection  of  infundibulin       .     318 


INTRODUCTION 

After  many  centuries  spent  in  unprofitable  speculation  and 
fruitless  investigation,  the  far-reaching — the  vital— importance 
of  the  Pituitary  has  at  last  come  to  be  fully  recognized. 

To  those  who  have  made  a  study  of  the  history  of  the  sub- 
ject the  extraordinary  vicissitudes  that  have  accompanied  the 
acquisition  of  our  knowledge  of  the  Pituitary  Body,  and  the 
strange  lapses  into  oblivion  when  recognition  of  its  importance 
seemed  within  our  grasp,  are  almost  incredible.  For  ages  a 
subject  of  curiosity  and  of  strange  beliefs — as  witness  the  very 
name,  derived  from  pituita,  meaning  phlegm,  which  by  Galen  and 
other  ancient  writers  it  was  supposed  to  secrete  into  the  nasal 
cavity1 — this  structure  is  now  the  object  of  the  keenest  scientific 
interest. 

The  Pituitary  Body  is  an  organ  of  internal  secretion,  and  is, 
as  we  shall  see  later,  of  vital  importance  to  the  animal  organism. 

The  phenomenon  of  internal  secretion,  or  hormonopoiesis,  is 
fully  recognized  in  regard  to  many  individual  hormonopoietie 
organs  ;  but  the  problem  of  the  correlation  of  the  internal  se- 
cretions of  the  coordinated  system  of  hormonopoietie  organs,  of 
which  the  Pituitary  forms  a  part,  is  very  complicated,  and  for 
the  most  part  imperfectly  understood,  although  it  is  now  acknow- 
ledged by  most  authorities  that  this  correlation  is  a  close  one, 
and  that  the  influence  of  any  one  of  the  hormonopoit  t  ic  organs 
on  the  metabolism  cannot  be  completely  considered  aparl  from 
the  interaction  of  the  rest. 

1  Vieussens,  Sylvius,  and  other  ancient  writers  considered  thai  the  Pituitary 
was  concerned  in  the  formation  of  the  cerebrospinal  fluid.  Commenting  on  this 
view  Cushing  calls  attention  to  the  fact  that  cerebrospinal  fluid,  which,  following 
Herring,  he  thinks  receives  secretion  directly  from  the  Pituitary,  m a\  in  certain 
pathological  circumstances  escape  from  the  nose. 

Richard  Lower,  in  a  tract  (Dissertatio  tie  Origine  Catarrhi)  published  in  l<iT2. 
makes  the  following  inspired  statement:  "For  whatever  serum  is  separated  into 
the  ventricles  of  the  brain  and  tissues  out  of  them  through  the  infundibulum  to 
the  glandula  pituitaria  distils  not  upon  the  palate  but  is  poured  again  into  the 
blood  and  mixed  with  it."  This  declaration  seems  to  give  to  Riohard  Lowei 
priority  in  regard  to  the  hypothesis  of  internal  secretion. 

1 


2  THE   PITUITARY 

Before  we  proceed  to  the  study  of  that  part  of  the  hormono- 
poietic  system  known  as  the  Pituitary  Body,  it  will  be  advisable 
to  state  and  to  define  some  of  the  special  terms  that  will  be 
used.  This  seems  particularly  necessary,  for  in  the  literature  of 
the  subject  we  find  that  many  authors  are  not  clear  or  precise 
in  regard  to  the  terms  they  employ.  For  instance,  Fischer  is 
very  confusing  in  his  use  of  the  word  '  hypophysis '.  It  is  some- 
times difficult  to  discover  whether  by  this  term  he  is  referring 
to  the  whole  Pituitary  Body  or  only  to  the  anterior  portion 
(vorderlappen). 

By  the  term  '  hypophysis  '  (vtro-fyvuv  =  to  grow  under)  that 
portion  of  the  Pituitary  which  is  derived  from  the  buccal  ecto- 
derm will  be  implied,  for  this  part  of  the  Pituitary  grows  under 
the  encephalon  ;  consequently  the  word  'hypophysis',  strictly 
speaking,  refers  to  the  epithelial  portions  of  the  Pituitary — the 
pars  anterior  and  the  pars  intermedia- — and  should  only  be  used 
in  this  connexion.  Since  no  extract  is  made  from  the  pars 
anterior  and  the  pars  intermedia  together  and  alone,  the  term 
'  hypophysin  ',  which  is  commonly  used,  has  no  meaning. 

By  the  terms  '  pars  anterior '  and  '  anterior  lobe '  is  meant 
that  part  of  the  Pituitary  which  lies  anteriorly  in  the  human 
subject,  and  is  separated  from  the  rest  of  the  organ  by  the  cleft. 
This  portion  of  the  Pituitary,  which  is  epithelial  in  structure, 
has  been  called  by  comparative  histologists  the  '  distal  epithelial 
portion ',  because  the  position  of  it  in  relation  to  the  rest  of  the 
Pituitary  varies  in  different  animals,  so  much  so  that  it  may  be 
situated  inferiorly,  and  even  posteriorly. 

The  '  pars  intermedia '  is  formed  by  the  epithelial  investment 
of  the  pars  nervosa  and  of  the  neck,  or  stalk,  of  the  Pituitary. 
By  comparative  histologists  this  portion  of  the  Pituitary  has 
been  described  as  the  '  juxtaneural  epithelium '. 

The  '  pars  nervosa  '  is  that  part  of  the  Pituitary  which  is 
derived  from  the  nervous  system  (infundibular,  or  neural,  process). 

The  pars  nervosa  and  pars  intermedia  together  constitute  in 
the  human  subject  the  '  posterior  lobe  ',  or  '  pars  posterior  '.  This 
division  into  the  anterior  and  posterior  lobes  arose  no  doubt  from 
the  ease  with  which  they  can  be  separated  the  one  from  the  other 
on  coarse  dissection. 

By  the  term  '  infundibulin  '  is  denoted  the  extract  made  from 
the  posterior  lobe. 


PART    I 

THE    MORPHOLOGY 

OF 

THE    PITUITARY 


PART   I 

THE   MORPHOLOGY   OF  THE   PITUITARY 

§i.     DEVELOPMENT   OF   THE   PITUITARY 

The  scientific  study  of  the  pituitary  may  be  said  to  date  from 
the  year  1838,  when  Rathke1  first  described  the  mode  of  origin 
of  the  hypophysis  from  the  primitive  alimentary  tract.  He 
considered,  however,  that  the  pouch  described  by  him  was 
entodermie  in  origin.  Since  that  time  numerous  workers  have 
confirmed,  modified,  and  extended  his  observations ;  and  our 
present  settled  knowledge  of  the  development  of  the  pituitary 
has  been  due — apart  from  the  work  of  Rathke — chiefly  to  the 
labours  of  Balfour2,  Mihalkovics3,  Gotte4,  Kupffer5,  and  Herring6. 
Many  other  investigators  have  studied  this  question,  and  diverse 
views  have  been  held  as  to  the  origin  of  the  epithelial  portion  of 
the  pituitary  :  whether  it  be  entirely  derived  from  the  buccal 
ectoderm,  or  from  the  entoderm  of  the  foregut  in  whole  or  in 
part  ;  or  even  whether  it  may  not  arise  to  some  extent  from 
the  wall  of  the  cerebral  vesicle.  Still,  it  is  generally  believed 
that  the  two  distinct  parts  of  the  pituitary — the  neural  and  the 
epithelial — almost  certainly  arise  from  different  sources,  although 
ultimately  they  come  into  very  intimate  relationship. 

The  earliest  stage  at  which  the  develojnnent  of  the  human 
pituitary  can  be  recognized  is  in  the  foetus  about  2*5  mm.  in 
length,  when  the  hypophysis  is  represented  by  what  is  known 
as  the  hypophysial  angle  (fig.  1).     This  angle  is  produced  by  the 

1  Rathke,  H.,  Arch.  f.  Anat.  Physiol,  u.  Wissensch.  Med.,  1838,  v,  482. 

2  Balfour.  F.  M.,  Quart.  Journ.  Micr.  ScL,  1874,  xiv,  362. 

3  Mihalkovics,  V.  von,  Arch.  f.  Milcr.  Anat.,  1875,  xi,  389. 

4  Gotte,  A.,  Entwickelungsgesch.  der  Unlce,  Leipz.,  1875.  Abstract  :  Jahr.  d. 
Anal.  u.  Physiol.,  Leipz.,  1878,  v,  541. 

5  Kupffer,  C.  von,  Sitz.  d.  Gcsellsch.  f.  Morphol.  u.  Physiol,  1894,  Munchen 
(1895),  59. 

6  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908.  i,  161. 


4  MORPHOLOGY 

junction  of  the  upper  limit  of  the  pharangeal  membrane  with  the 
roof  of  the  primitive  stomodeum.  When  this  membrane  breaks 
down  the  hypophysial  angle,  which  is,  as  was  first  shown  by 
Balfour1,    ectodermal    in     origin,    becomes    deepened     to     form 

Rathke's  pouch  (figs.  2  and 
3).  Miller2,  however,  who  has 
recently  investigated  the  de- 
velopment of  the  pituitary  in 
the  pig,  believes  that  the 
ectodermal  portion  of  the 
pituitary  is  formed  from  the 
'  bra  in- wall  '  as  well  as  from 
the  buccal  cavity — at  any 
rate  in  the  species  examined. 
Behind  the  upper  portion 
of  the  disappearing  pharangeal 
membrane  another  angle,  or 
pouch,  is  produced  at  the 
highest  limit  of  the  foregut. 
This  is  known  as  the  pouch 
of  Seessel3  (figs.  1  and  2),  and 
it  is  entodermal  in  origin. 
Saint  -  Remy4  and  Kupffer5 
thought  that  there  is  some 
connexion  between  Rathke's 
and  Seessel 's   pouches  in  the 

_..  ,  ,.  early  stages  of   development, 

Diagram  to  show  earliest  stage  in  the  ,         7  .      . 

development  of  the  pituitary.  R,  hypo-  but  that  in  the  adult  pituitary 
physiai  angle;  P,  pharangeal  membrane;  Gf  mammals  onlv  a  rudiment 
S,    Seessel's   pouch ;    N.   notocord.     (After       ,    ,,  ,         "  ,  .   , 

Mihalkovics  and  Herring.)  ot  the  entodermal   vesicle  re- 

mains. 
Dursy6  believed    that    the    anterior  lobe    is    entirely  derived 
from  the  foregut,  as  did  Valenti7,    who    described   the   anterior 


Fig  1. 


1  Balfour,  F.  M.,  Quart  Journ.  Micr.  Sci.,  1874,  xiv,  362. 

2  Miller,  W.  W.,  Anat.  Record  (Proc.  Amer.  Assoc.  Anat.),  1916,  x,  226. 

3  Seessel,  A.,  Arch.  Anat.  u.  Physiol,  1877,  Anat.  Abth.,  449. 

4  Saint-Remy,  G.5  Compt.  Rend.  Soc.  Biol,  1895,  ii,  423. 

5  Kupffer,  C.  von,  Bite,  d,  Gesellsch.f.  Morphol.  u.  Physiol,  1894,  Munchen  (1895),  59. 

6  Dursy,  E.,  Zur  EntwicMungsgesch.  d.  Kopjes,  Tubingen,  1869,  76. 

7  Valenti.  G.;  Anat.  Anz.,  1895,  x,  538. 


DEVELOPMENT   OF   THE   PITUITARY 


lobe  in  amphibians  as  being  developed  from  the  entodermal 
tissues  behind  Seessel's  pouch.  But  this  suggestion  has  few 
supporters  in  the  present  day,  although  recently  Miller1  has 
come  to  the  conclusion  that  the  epithelial  portion  is  derived 
partly  from  the  ectoderm  and 
partly  from  the  entoderm. 

The  view  of  Dohrn2  and 
others  as  to  the  origin  of 
Rathke's  pouch  from  the  re- 
mains of  a  preoral  gill-cleft 
has  no  modern  adherents. 

Reichert3  and  His4  origin- 
ally expressed  the  opinion 
that  the  notocord,  which 
bends  over  the  upper  limit 
of  Seessel's  pouch,  and  comes 
into  close  relationship  with 
Rathke's  pouch  (figs.  1  and 
2),  either  takes  part  in  the 
formation  of  the  hypophysis 
or  influences  the  invagination 
of  Rathke's  pouch.  Eventu- 
ally they  gave  up  this  view, 
and  it  is  now  considered  cer- 
tain by  most  authorities  that 
at  the  most  the  notocord 
simply   limits  the    backward 

extension  of  Rathke's  pouch.  Diagram  to  show  second   stage   in   the 

Tijr-ii      i  ,i     i  i    •  development   of   the  pituitary.      I,   infun- 

Miller1,    nevertheless,    claims    dibulum .    R,    Rath£'s    pouch;    P,    re- 

to  have  shown  that  in  the  pig     mams     of      pharangeal     membrane ;       S, 

embryo  the  notocord  not  only    *«J8  .  Pouc^  '     Nr    n°tocord-      {After 

J  "'      Mihalkovics  aim  Herring. ) 

influences  the  development  of 

the  hypophysis,  but  actually  contributes  to  the  formation  of  the 
pars  anterior.  This  observer,  therefore,  is  in  agreement  with 
almost  every  view  that  has  been  put  forward  in  regard  to  the 
source  or  sources  of  the  epithelial  elements  of  the  pituitary.     It 

1  Miller,  W.  W.,  Anat.  Record  (Proc.  Amer.  Assoc.  Anat.),  1916,  x,  226. 

2  Dohrn,  A.  L.,  Mittheilung.  d.  Zool.  Station  zu  Neapel,  1884,  iii,  252. 

3  Reichert,  K.  B.,  Das  Entwickelungsleben  im  Wirbeltier- Reich,  Berlin,  1840,  179. 

4  His,  W.,  Untersvch.  u.  die.  erste.  Anlage  d.  Wirbeltierleibs.   Leipz.,  1868,  135. 


Fig.  2. 


6  MORPHOLOGY 

may,  however,  be  taken  as  generally  accepted  that  in  most 
mammals  the  epithelial  parts  ot  the  pituitary  are  derived  only 
and  entirely  from  Rathke's  pouch,  which  is  a  mesial  invagination 
from  the  stomodeum,  and  is,  therefore,  as  already  mentioned, 
ectodermal  in  origin. 

The  further  steps  in  the  development  of  the  pituitary  are 
more  easily  followed,  owing  to  the  clearer  definition  of  the 
structures  found  in  the  larger  embryos. 


/V ".'*'•* •'.'-••:" •••-,.  •'  -;'.'. '..  '",v<,2.^: 


Fig.  3. 


Section  of  the  head-end  of  a  foetus  4  mm.  hi  length,  showing  Rathke's  pouch. 
(From  a  section  kindly  lent  by  J.  E.  Frazer.) 

X  60. 

In  the  earliest  stages,  which  have  already  been  described, 
there  is  no  connective  tissue  between  the  cerebral  vesicle  and 
the  buccal  epithelium  ;  consequently  a  very  close  union  is 
formed  between  these  two  parts,  and  the  juxtaposition  of  the 
structures  concerned  is  maintained  during  the  subsequent  stages 
in  the  development  of  the  pituitary  (figs.  4  and  5). 

According  to  Herring1,  when  the  hypophysial  angle  becomes 

1  Herring,  P.  T.,  Quart.  Joum.  Exw,r.  Physiol.,  1908,  i,  161. 


DEVELOPMENT   OF   THE   PITUITARY  7 

deepened  into  a  definite  pouch  by  the  bending  forwards  of  the 
stump  of  the  pharangeal  membrane,  which  causes  the  upper 
surface  of  the  angle  to  curve  backwards  and  downwards,  a 
portion  of  the  adherent  cerebral  vesicle  is  dragged  down  and 
forms  a  hollow  process  behind  the  pouch.  This  cerebral  recess 
represents  the  first  appearance  of  the  infundibular,  or  neural, 
process  (fig.  2).  Mihalkovics1  was  probably  the  first  to  show 
that  the  neural  process  is  derived  from  the  diencephalon. 


■-■■         -■  ■■••••..  •  •    ..  -  ■  - 


Fig.  4, 

Section  of  the  stomodeum  and  encephalon  of  a  human  foetus  9  mm.  in  length, 
showing  Rathke's  pouch.     (From  a  section  kindly  lent  by  J.  E.  Frazer.) 

X60. 

That  the  same  course  of  events  is  followed  in  all  mammals 
is  doubtful.  The  general  contour  and  the  relation  of  the 
epithelial  portions  to  the  neural  process  in  the  fully  developed 
pituitary  vary  so  much  in  different  mammals  that  more  work 
is  required  in  regard  to  comparative  embryology  before  Herring's 
description — accurate  so  far  as  it  goes — of  the  formation  of  the 
infundibular  process  in  the  cat  can  be  accepted  as  being 
invariable. 

1  Mihalkovies,  V.  von,  Arch.  f.  Mikr.  Anat,  1875,  xi,  389. 


8  MORPHOLOGY 

The  next  step  in  the  development  of  the  pituitary  consists 
of  the  constriction  of  the  neck  of  Rathke's  pouch,  which  ulti- 
mately becomes  completely  closed  by  development  of  the  sphen- 
oid cartilage.  A  column  of  cells  may  remain,  however,  for 
some  time,  and  mark  the  situation  of  the  neck  of  the  pouch 
(fig.    5).       Not    infrequently   a   collection   of  these   cells   persists 


Diagram  to  show  the  development  of  the  infundibular  process  and  the  occlusion 
of  the  neck  of  Rathke's  pouch.  (After  Herring.)  B,  cavity  of  the  encephalon; 
C,  column  of  cells  marking  the  neck  of  Rathke's  pouch ;  I,  infundibulum ; 
R,  residual  lumen  of  the  hypophysis ;  PA,  pars  anterior,  or  distal  epithelium ; 
PI,  pars  intermedia,  or  juxtaneural  epithelium. 


throughout   life   and   has  been   known   to   constitute   the  source 
of   a    neoplasm    in   the   adult  ;    Haberfeld1,   indeed,   asserts  that 
epithelial  cells  are  invariably  to  be  found  so  embedded,  forming 
what  he  and  other  German  writers  call  the  rachendachhypophy.se. 
The  further  stages  of  development  are  well  defined  and  may 

1  Haberfeld,  W.,  Zeiglefs   Beitr.   &    Pathol.    Anat.   v.   z.    Allg.    Pathol,    1909, 
xlvi,  133. 


DEVELOPMENT   OF   THE   PITUITARY  9 

conveniently  be  studied  in  the  human  embryo  about  16  mm. 
in  length,  although  the  details  are  not  quite  the  same  in  all 
mammals.  Figures  6,  7  and  8  show  different  aspects  from  the 
same  specimen — a  16-mm.  foetus — of  the  developing  connexion 
between  the  hypophysis  and  the  infundibular  process  of  the 
cerebral  vesicle.  Most  anteriorly  (fig.  6)  the  cavity  of  the 
hypophysis  is  triradiate — the  superior  diverticulum,  or  process, 
of  the   cavity   being,    as   it   were,    more   or   less   independent    of 


; 
.    ■ 


■ 


Fig.  6. 

Section  of  the  pituitary  region  of  a  human  foetus  16  mm.  in  length,  showing 
the  infundibular  process  meeting  the  triradiate  cavity  of  Rathke's  pouch  which  is 
now  shut  off  from  the  stomodeum.     {From  a  section  kindly  lent  by  J.  E.  Frazer.) 

X60. 

the  cerebral  vesicle  above.  In  figure  7  the  infundibular  process 
is  seen  to  be  in  close  relationship  with  the  middle  portion  of 
the  hypophysis  :  the  superior  diverticulum  of  the  cavity  has 
disappeared,  and  the  infundibular  process  has  become  flattened 
out  on  the  top  of  the  hypophysis.  Further  back  still  (fig.  8)  we 
find  that  the  infundibular  process  has  grown  down  past  the  back 
of  the  hypophysis,  and  that  the  sides,  or  lateral  'horns',  of  this 
structure  have  encircled  the  descending  process,  in  the  manner 


10  MORPHOLOGY 

described  by  Frazer1.  Figure  9  represents  diagrammatically 
composite  side  and  back  views  of  these  relationships.  Sub- 
sequently the  infundibular  process  becomes  more  intimately 
blended  with  the  hypophysis  ;  and  gradually  in  the  human 
subject,  and  in  most  mammals,  the  central  cavity  disappears 
except,  perhaps,  for  a  small  pouch  of  the  cerebral  vesicle  at 
the  neck.     In  the  cat  the  central  cavity  persists. 


. 


■  - 


Fig.  7. 

Section  of  the  pituitary  region  of  a  human  foetus  16  mm.  in  length,  serial 
to  but  further  back  than  the  section  shown  in  figure  6.  The  infundibular  process 
is  spread  out  over  the  middle  portion  of  the  occluded  pouch  of  Eathke.  {From 
a  section  kindly  lent  by  J.  E.  Frazer. ) 

X  60. 

In  the  human  foetus  75  mm.  in  length  the  pituitary, 
embedded  in  delicate  connective  tissue,  is  found  to  be  lying 
in  a  deep  cartilaginous  depression — the  primitive  sella  turcica 
(fig.  10).  At  this  stage  of  development  all  trace  of  the  neck 
of  Rathke's  pouch  has  in  normal  circumstances  disappeared, 
although,  as  already  stated,  a  collection  of  cells  may  be  enclosed 
in  the  sphenoid. 

1  Frazer,  J.  E.,  Lancet.  1912,  ii,  875. 


DEVELOPMENT   OF   THE   PITUITARY  11 

There  are  several  points  of  interest  to  be  noted  in  regard  to 
the  final  stages  in  the  formation  of  the  pituitary.  We  find  that 
the  hypophysis,  which  originally  formed  a  simple  sac  and  later 
a  triradiate  cavity,  increases  in  size  by  means  of  diverticula 
branching  out  anteriorly  and  laterally  from  the  residual  lumen. 
In  this  way  the  hypophysis  becomes  a  much  enlarged  racemose 
body.     In  cross-section,  therefore,  at  this  period  the  hypophysis 


4!*>    .^r. 


Fig.  8. 

Section  of  the  pituitary  region  of  a  human  fcetus  16  mm.  in  length,  serial  to 
but  further  back  than  the  section  shown  in  figure  7.  The  infundibular  process 
has  descended  between  the  lateral '  horns '  of  the  isolated  Rathke's  pouch.  (From 
a  section  kindly  lent  by  J.  E.  Frazer.) 

X60. 

is  seen  (fig.  10)  to  be  closely  related  to  a  solid  neural  process. 
The  main  part  of  the  hypophysis — that  is,  the  distal  epithelial 
portion,  or  pars  anterior — has  a  glandular  appearance  owing  to 
the  mode  of  growth  already  described  ;  and  the  residual  lumen 
of  the  hypophysis — the  remains  of  Rathke's  pouch  from  which 
diverticula  can  be  traced,  is  closely  applied  on  its  posterior 
surface  to  the  neural  process.  This  thin  posterior  wall  of  the 
central    cavity    of    the    hypophysis    eventually    forms    the    pars 


12 


MORPHOLOGY 


A 


U 


B 


Diagrammatic  representations  of  the  pituitary  of  a  human  foetus  16  mm.  in 
length  seen  in  sections  in  figures  6,  7,  and  8. 

A.  Side-view. 

B.  Back- view. 

C.  Sectional  side-view:  a,  line  of  vertical  transverse  section  seen  in  figure  6; 
b,  line  of  vertical  transverse  section  seen  in  figure  7  ;  c,  line  of  vertical  transverse 
section  seen  in  figure  8. 


DEVELOPMENT   OF   THE   PITUITARY  13 

intermedia,  or  juxtaneural  epithelium  (see  fig.  5).  It  will  also 
be  observed  in  the  section  (fig.  10)  that  the  lateral  '  horns  '  of 
the  hypophysis  have  encircled  the  neck  of  the  infundibulum  ; 
and  that  the  pars  anterior  extends  well  in  front  of  the  infundib- 
ular process  (compare  with  figs.  6,  7,  8). 


ft*        v.x% 

•*■«       •'■■■■:    I  *--  ■...■  S  ska 


Fig.  10. 
Section  of  the  pituitary  of  a  human  foetus  75  mm.  in  length. 


X  60. 


Ultimately  in  mammals  the  branching  processes  of  the  pars 
anterior  fuse,  or  become  compressed  together,  to  produce  a  more 
or  less  compact  structure.  In  elasmobranchs  this  tubular,  or 
branching,  arrangement  is  the  final  state  of  development. 

The  last  stages  in  the  formation  of  the  pituitary  in  mammals 
are  unimportant  developmentally.  As  we  shall  see,  certain 
variations  of  configuration  occur  in  the  different  orders  ;  con- 
sequently the  fully  developed  organ  can  best  be  described  from 
anatomical — general  and  comparative — points  of  view. 


§ii.     ANATOMY   OF    THE   PITUITARY 


MACROSCOPICAL    ANATOMY 

The  actual  conformation  of  the  pituitary  and  of  the  bony  bed 
in  which  it  is  situated  varies  considerably  in  different  animals, 
but  in  all  there  is  a  close  relationship  between  the  two  so  far 
as  their  outlines  are  concerned. 

General  characteristics. — If  the  fresh  pituitary  be  cut  in 
transverse  section  the  anterior  lobe  is  found  to  be  soft  but  tough 
in  consistence,  and  pink  or  yellowish-pink  in  colour,  in  marked 
contrast  with  the  posterior  lobe  which  is  very  soft  and  paste-like, 
and  pearly  white  in  colour. 

In  all  mammals  the  pars  anterior,  or  distal  epithelial  portion, 
is  much  larger  than  the  pars  posterior  ;  but  the  relationship  of 
the  two  parts  the  one  to  the  other  varies  in  the  different  orders, 
as  we  shall  see  later. 

In  the  human  subject,  the  posterior  aspect  of  the  pars  anterior 
tits  like  a  cap  on  the  convex  anterior  surface  of  the  pars  posterior 
(fig.  11)  ;  the  two  lobes  are  separated  by  a  narrow  cleft,  which, 
as  already  stated,  represents  the  residual  lumen  of  Rathke's 
pouch  ;  and  the  pars  nervosa  is  covered  in  varying  degrees  in 
front  and  laterally  by  the  epithelium  of  the  pars  intermedia 
(juxtaneural  epithelium).  In  man  the  pars  nervosa  is  solid, 
the  central  cavity  having  disappeared  in  the  process  of  develop- 
ment. The  anterior  and  posterior  lobes  are  easily  disjoined  by 
coarse  dissection. 

The  dimensions  and  weight  of  the  pituitary. — The  dimen- 
sions and  weight  of  the  pituitary  vary  somewhat  in  different 
individuals  of  the  same  species,  and  these  variations  are  de- 
pendent   on    the    age,    and    to    some   extent    on    general    bodily 


ANATOMY    OF   THE   PITUITARY  15 

development.  But  in  spite  of  this  general  relationship  between 
the  size  of  the  body  and  the  size  of  the  pituitary,  the  interest- 
ing and  important  fact  has  been  noted  that  the  pituitary  is 
relatively  larger  in  adult,  parous  females,  especially  in  multi- 
parse,  than  in  nulliparae  and  in  males. 

In  regard  to  the  weight  of  the  pituitary,  Caselli1  found  that 
in    fifty    men    the    average    weight    of    the    pituitary   was    0*667 


Fig.  11. 

Median  horizontal  section  of  the  adult  human  pituitary.  The  pars  anterior 
is  below,  and  the  pars  nervosa  above. 

X  5. 

gramme,  and  in  fifty  women   0*731   gramme.     The  material  for 
this  investigation  was  obtained  from  asylums. 

Halliburton,  Candler,  and  Sykes2  found  that  in  eighteen  adult 
males,  the  average  weight  of  the  fresh  pituitary  was  0*469 
gramme,  yet  in  only  four  cases  did  the  organ  weigh  more  than 
0*5   gramme.     On   the   other   hand,    in    twenty-four  females   the 

1  Caselli,  A.,  Studi  Anat.  e  Speriment.  Fisiopatologia  d.  Glandola  Pihiitaria. 
Reggio  nell'  Emilia,  1900. 

2  Halliburton,  W.  D.,  J.  P.  Candler,  and  A.  W.  Sykes,  Quart.  Journ.  Exper. 
Physiol ..  1909,  ii,  229. 


16  MORPHOLOGY 

average  weight  of  the  fresh  gland  was  0*567  gramme,  and  in 
only  four  of  these  cases  did  the  organ  weigh  less  than  0*5 
gramme.  All  the  material  used  in  this  investigation,  also,  was 
obtained  from  asylums. 

Erdheim  and  Stumme1,  in  an  extensive  study  of  this  question, 
obtained  the  following  results  with  regard  to  the  gravimetrical 
differences  in  human  pituitaries. 

In  males  during  the  second  decade  of  life  the  average  weight 
was  found  to  be  0*563  gramme  ;  during  the  third  decade,  0*593 
gramme;  and  during  the  fourth  decade,  0*643  gramme.  In  the 
later  years  of  life  the  weight  of  the  pituitary  was  observed 
gradually  to  decrease.  With  regard  to  females,  these  observers 
found  that  in  nulliparae  the  average  weight  of  the  pituitary  was 
approximately  the  same  as  in  men  ;  and  the  maximum  weight 
obtained  during  the  reproductive  period  was  0*75  gramme.  In 
primiparae  recently  confined  the  average  weight  was  0*847  gramme ; 
whilst  in  multiparas  at  the  end  of  pregnancy  the  average  weight  was 
1  *06  gramme.  The  maximum  weight  found  in  a  primiparous  woman 
was  1*10  gramme,  and  in  a  multiparous  woman  1*65  gramme. 

Li  von2,  also,  has  summarized  his  own  investigations  and  those 
of  previous  observers  concerning  the  weights  and  sizes  of  the 
pituitary  in  Man  and  in  the  commoner  mammals.  Here  we  are 
only  concerned  with  these  questions  in  reference  to  the  human 
subject,  for  it  is  usual  for  scientific  investigators  to  make  their 
own  control  observations  concerning  such  matters  in  connexion 
with  their  experimental  studies. 

Livon's  observations  were  made  on  pathological  material  ; 
consequently,  as  he  himself  points  out,  they  are,  possibly,  not 
of  much  value.  This  objection,  however,  obtains  in  practically 
all  the  investigations  that  have  been  made  on  this  subject. 
Further,  in  the  collected  statistics  given  by  this  author  no 
mention  is  made  of  sex-distinctions  ;  and  this  omission  renders 
the  figures  quite  valueless  in  the  light  of  modern  knowledge. 

Schonemann3,  Comte4,  and  others  have  noted  that  the 
weight  of  the  pituitary  in  Man  varies  according  to  the  age  ;    and 

1  Erdheim,  J.,  and  E.  Stumme,  Beitr.  z.  Pathol.  Anal.  u.  z.  Allg.  Pathol,  1909 
xlvi,  1. 

2  Livon,  Ch.,  Marseille  Mddical,  1909  (No.  22),  683. 

3  Schonemann,  A.,  Virchow's  Arch.  f.  Pathol.  Anat.  n.  Physiol.,  1892,  cxxix,  310. 

4  Comte,  L.,  Beitr.  z.  Pathol.  Anat.  u.  z.  Allg.  Pathol,  1898,  xxiii,  90. 


gr. 

013 

55 

0-30 

55 

0-53 

55 

0'60 

•    •                       55 

0-67 

ANATOMY   OF   THE   PITUITARY  17 

the  approximate  figures  derived  from  these  studies  are  as 
follows  : — 

New-born  infant 
From  1  to  10  years 
From  10  to  20     ., 
From  20  to  30     ,, 
From  30  to  40     „ 

But  in  regard  to  these  estimations,  also,  no  allowance  appears 
to  have  been  made  for  sex-differences,  so  the  figures  are  of 
value  only  in  that  they  show  the  relative  increases  of  weight 
with  age  up  to  a  certain  period.  After  middle  life  most 
investigators  agree  that  there  is  a  gradual  decline  in  the  average 
weight  of  the  pituitary. 

It  will  be  seen  that  there  is  some  discrepancy  between  the 
various  sets  of  figures  recorded  above,  even  when  sex  was  taken 
into  consideration ;  but  it  is  possible  to  account  for  this  by  assum- 
ing that  the  different  observers  employed  different  methods  for 
collecting  their  material.  The  outstanding  fact,  however,  is  the 
influence  of  pregnancy  in  causing  an  increase  in  the  weight  of 
the  organ.  We  shall  have  to  consider  this  matter  again  when 
studying  the  histology  of  the  pituitary  in  relation  to  its  functions. 

The  dimensions,  like  the  weight,  of  the  normal  human  pituitary 
appear  to  vary  somewhat.  Livon1  gives  the  following  table  of 
measurements,  which  was  compiled  from  various  sources  : — 


teroposterior 
diameter. 

mm. 

6-8 
8 

Vertical 

diameter. 

mm. 

6-8 

6 

Transverse 

diameter. 

mm. 

12 

12-15 

Authors. 

Sappey 
Testut 

5-7 

5-7 

15 

Poirier 

6-8 

6 

12-15 

Thaon 

8 

6 

12-15 

Paulesco 

10 

5-5 

15 

Livon 

Here,  again,  we  find  some  divergence  in  the  figures,  and  this 
is  no  doubt  due  to  an  uneven  admixture  of  the  sexes  and  patho- 
logical conditions  present,  and  possibly  to  the  employment  of 
different  methods  of  measurement. 

Erdheim    and    Stumme2,   also,   record    their    observations   on 

1  Livon,  Ch.,  Marseille  Medical,  1909  (No.  22),  683. 

2  Erdheim,  J.,  and  E.  Stumme,  Beilr.  z.  Pathol.  Anal.  u.  z.  Allg.  Pathol., 
1909,  xlvi.  1. 


18  MORPHOLOGY 

this  point.  These  investigators  give  the  following  average  figures 
for  adult  men  :  transverse  diameter,  14*4  mm.  ;  anteroposterior 
diameter,  11*5  mm.1;  and  vertical  diameter,  5  5  mm.  In  nulli- 
parous  adult  women  the  average  measurements  were  found  to 
be  14*4  mm.,  11*5  mm.,  and  5*9  mm.  respectively. 

These  figures  show  that  the  dimensions,  like  the  weights,  are 
almost  identical  in  adult  men  and  nulliparous  adult  women  ;  but 
they  differ  considerably  from  some  of  the  collected  figures  given 
by  Livon. 

The  sella  turcica  and  the  anatomical  relations  of  the 
pituitary. — -The  fully  developed  pituitary  is  an  intracranial 
organ,  the  epithelial  part  derived  from  the  ectoderm  of  the 
stomodeum  having  become  completely  shut  off  at  a  very  early 
period  from  the  buccal  cavity  by  the  development  of  the 
cartilage  in  which  the  basisphenoid  bone  is  laid  down.  In 
this  way  the  pituitary  comes  to  lie  on  the  body  of  the  sphenoid 
in  a  recess  known  as  the  '  sella  turcica  '  (Turk's  saddle)  owing  to 
its  shape  :  the  cavity  is  hollowed  out  in  the  centre  from  before 
backwards,  and,  in  the  human  subject,  slopes  away  at  the  sides, 
while  the  saddle-like  appearance  is  further  emphasized  by  the 
anterior  and  posterior  clinoid  processes  which  overhang  the 
seat  of  the  '  saddle  '  before  and  behind  (fig.  12). 

It  is  obvious  that  the  size  of  the  pituitary  is  definitely 
related  to  the  dimensions  of  the  sella  turcica,  but  very  few 
accurate  observations  have  been  made  on  the  capacity  of  this  fossa. 

Gibson2,  in  an  examination  of  107  skulls,  found  that  there 
are  normally  very  considerable  variations  in  the  size,  shape, 
and  bony  relations  of  the  sella  turcica.  The  average  dimensions 
of  this  fossa — that  is,  of  one  reconstructed  from  all  the  fossae 
examined — were  found  to  be  12  mm.  in  the  anteroposterior 
diameter,  and  6  mm.  in  the  vertical. 

Cope3  examined  fifty  skulls  and  obtained  the  following 
average  figures  in  regard  to  the  size  of  the  sella  turcica  :  the 
anteroposterior  diameter  measured  10-94  mm.,  the  transverse 
diameter  11*02  mm.,  and  the  vertical  diameter  5-82  mm. 

1  In  the  original  paper  there  is  a  misprint  or  miscalculation  in  the  average 
figure,  which  is  stated  to  be  21*5  mm.     This  error  has  been  copied  by  Biedl. 

2  Gibson,  W.  S.,  Surg.  Qyncecol.  ObsteL,  1912,  xv,  199. 

3  Cope,  V.  Z.,  Brit.  Journ.  Surg.,  1916,  iv,  107. 


ANATOMY   OF   THE   PITUITARY 


19 


According  to  Gushing1,  the  average  measurement  of  the  sella 
turcica  as  seen  in  a  skiagram — obviously  an  imperfect  method 
— are  as  follows  :  the  anteroposterior  diameter  is  about  15  mm., 
and  the  depth  of  the  fossa  about  9  mm.     These  measurements 


Fig.  12. 

The  base  of  the  skull  in  the  human  subject  with  a  normal  sella  turcica. 

(Photograph.)         X  ], 

appear  to  err  on  the  generous  side,  for  a  majority  of  X-ray 
photographs  show  that  the  sella  turcica  is  of  a  smaller  size 
(fig.  13a),  although  the  larger  may  be  normal  (fig.  13b).     X-ray 

1  Cushing,  H..  The  Pituitary  Body  ami  its  Disorders,  1912. 


20 


MORPHOLOGY 


Fig.  13a. 
Radiograph  of  a  normal  sella  turcica  in  the  living  human  subject, 
posterior  diameter  measures  11  mm.     (By  Thurstan  Holland.) 


The  antero- 


Fig.   13b 

Radiograph  ot  a  normal  sella  turcica  in  the  living  human  subject.  The  antero- 
posterior diameter  measures  14-5  mm.  (This  excellent  photograph  was  taken  recently 
by  Thurstan  Holland  with  a  new  method  of  centering.) 

X}- 


ANATOMY    OF   THE    PITUITARY  21 

photographs,  therefore,  demonstrate  the  fact  that  even  in  per- 
fectly normal  individuals  there  is  a  considerable  degree  of 
variation  in  the  size  of  the  sella  turcica. 

Fitzgerald1  has  investigated  the  dimensions  of  the  sella  turcica 
in  over  100  skulls  of  both  sexes,  and  after  making  careful 
measurements  he  found  that  the  size,  and  to  a  less  extent  the 
shape,  of  the  pituitary  fossa  is  related  to  certain  measurements 
at  the  base  of  the  skull,  and  that  these  are  uninfluenced  by  sex. 

It  was  observed  that  if  measurements  be  taken  from  the 
tip  of  the  ethmoidal  spine  to  the  anterior  limit  of  the  optic 
groove  (anterior  measurement),  and  from  the  opisthion  to  the 
middle  of  the  sella  turcica  (posterior  measurement),  the  length 
of  the  pituitary  fossa  is  found  to  vary  directly  with  the  posterior 
measurement,  and  inversely  with  the  anterior  ;  that  is  to  say, 
a  long  anterior  measurement  and  short  posterior  are  associated 
with  a  short  fossa,  and  vice  versa. 

The  following  table,  to  which  appropriate  headings  have 
been  added,  of  the  average  measurements  of  the  sella  turcica 
in  relation  to  the  average  anterior  and  posterior  cranial 
measurements  mentioned,  taken  from  Fitzgerald's  paper,  illus- 
trates this  point,  and  also  shows  the  relation  of  these  measure- 
ments to  the  shape  of  the  fossa,  although  the  latter  is  subject 
to  variations. 

Table   I 

ON    ANTERIOR    MEASUREMENT 

Anterior  measurements  n«in+«i  „„„  „  „  „,  *      *     ,<    * 

basis  cranii.  Related  average  measurements  of  sella  turcica 


Length.  Breadth.  Front  depth.  Hind  depth. 

Large  (23-27)  mm.     .  .      10-5  mm.  17      mm.  8-5  mm.      7-7  mm. 

Medium  (20-23)  mm.        11      mm.  17 -5  mm.  7     mm.      6*5  mm. 

Small  (15-20  mm.)    ..      13     mm.  16*5  mm.  8     mm.      7     mm. 

ON    POSTERIOR    MEASUREMENT 


Posterior  measurements 
basis  cranii 


Related  average  measurements  of  sella  turcica. 


Length.  Breadth.  Front  depth.  Hind  depth. 

Large  (above  70  mm.)       14-5  mm.  17  mm.  7      mm.      7-5  mm. 

Medium  (65-70  mm.)         12      mm.  15  mm.  8      mm.      7     mm. 

Small  (under  65  mm.)        10      mm.  14  mm.  6*5  mm.      6-5  mm. 


The  measurements  basis  cranii  are  in  each  part  of  the  table 
divided  into  three  groups— large,  medium,  and  small. 

1  Fitzgerald,  D.  P.,  Joum.  Anal,  and  Physiol,  1910,  xliv,  231. 


22  MORPHOLOGY 

If  we  add  together  the  average  measurements  of  the  sellse 
turcica?  given  in  the  above  tables,  we  arrive  at  the  following 
approximate  average  dimensions  for  this  fossa  :  anteroposterior 
diameter,  11-8  mm.  ;  transverse  diameter,  15-1  mm.,  and  vertical 
diameter,  7*2  mm. 

It  is  difficult  to  explain  why  such  divergent  average  figures 
of  the  measurement  of  the  sella  turcica  have  been  obtained  by 
different  observers,  unless  different  methods  of  measurement  have 
been  employed. 

The  relation  of  the  sella  turcica  to  the  sphenoid  bone  and 
to  the  sphenoidal  cells  is  a  matter  of  considerable  anatomical 
interest,  and  also  of  surgical  importance  as  we  shall  see  later 
when  we  consider  the  methods  of  approach  to  the  pituitary. 

In  the  human  subject  the  pituitary  fossa  is  developed  in  the 
basisphenoid  (postsphenoid)  ;  but  in  some  animals,  such  as  the  pig, 
and  even  rarely  in  man,  the  presphenoid  may  take  part  in  the 
formation  of  the  anterior  wall  of  the  sella  turcica1. 

The  craniopharyngeal  canal,  which  becomes  occluded,  and  so 
causes  Rathke's  pouch  to  be  shut  off  from  the  oral  cavity, 
passes  through  the  anterior  part  of  the  basisphenoid,  a  fact  that 
has  been  emphasized  by  Haberfeld2,  Cope1,  and  others. 

The  sphenoidal  cells  are  very  inconstant  in  their  configuration 
and  their  relationship  to  the  pituitary  fossa  (fig.  14).  In  early 
life  the  sphenoidal  sinuses  are  small,  and  are  limited  to  the 
presphenoid3.  During  childhood  they  enlarge,  and  gradually 
the  presphenoid  becomes  hollowed  out.  The  development  of  the 
sinuses  may  stop  at  this  stage,  or  continue  until  the  postsphenoid 
is  either  partly  or  completely  excavated.  The  sella  turcica  may, 
therefore,  be  situated  behind,  or  partly  above  and  behind,  or 
even  completely  above,  the  sphenoidal  sinuses. 

There  is,  too,  considerable  variation  in  regard  to  the  septa 
which  may  divide  the  sphenoidal  cells.  As  a  rule,  the  sinuses 
are  situated  mostly  in  the  presphenoid,  and  are  divided  by  a 
median  anteroposterior  septum,  but  this  may  be  imperfect.  If 
the   sinuses   should  extend  back  into  the  postsphenoid,  there  is 

1  Cope,  V.  Z.,  Brit,  Joum.  Surg.,  1916,  iv,  107. 

2  Haberfeld,  W.,  Zeigler's  Beitr.  z.  Pathol.  Anat,  u.  z.  Allg.  Pathol.,  1909, 
xlvi,  133. 

3  Onodi,  A.,  The  Accessory  Sinuses  of  the  Nose  in  Children,  English  translation, 
1911. 


ANATOMY   OF   THE   PITUITARY 


23 


usually  a  transphenoidal  ridge  marking  the  line  of  junction  of  the 
two  parts  of  the  sphenoid  ;  but  horizontal  or  vertical  septa,  or 
both,  are  sometimes  found  dividing  the  sinuses  from  side  to  side 


Fig.   14. 

Macroscopical  sections  of  the  pituitary  regions  in  human  adults,  showing  varia- 
tions in  the  conformation  of  the  sella  turcica  and  the  related  sphenoidal  cells. 
(After  Gibson.) 

(fig.  14).  These,  as  we  shall  see  later,  may  give  rise  to  confusion 
in  regard  to  the  position  of  the  sella  turcica  during  surgical 
procedures. 


24  MORPHOLOGY 

The  cavity  of  the  sella  turcica  is  lined  with  dura  mater,  and 
it  is,  also,  covered  in  by  a  sheet  of  the  same  membrane,  which  is 
attached  to  the  four  clinoid  processes  and  perforated  for  the 
passage  of  the  stalk  of  the  posterior  lobe.  This  infundibular 
stalk  arises  from  the  floor  of  the  third  ventricle  at  the  site  of 
the  tuber  cinereum. 

Various  important  structures,  apart  from  those  just  mentioned, 
are  situated  in  immediate  relationship  to  the  pituitary.  The 
circular  sinus  completely  surrounds  the  organ.  This  sinus  is  com- 
posed of  the  cavernous  sinuses  on  either  side,  and  of  the  anterior 
and  posterior  communicating  channels.  The  sella  turcica  itself  is 
situated  in  the  centre  of  the  arterial  circle  of  Willis,  which  is 
formed  by  the  anterior  communicating  arteries  joining  the  anterior 
cerebral  arteries  in  front,  by  the  internal  carotids  and  posterior 
communicating  arteries  at  the  sides,  and  behind  by  the  posterior 
cerebral  arteries.  The  third  nerves  pass  from  behind  forwards 
and  above  downwards  on  either  side  in  close  proximity  to  the 
pituitary  ;  and  the  third,  fourth,  ophthalmic  division  of  the  fifth, 
and  the  sixth  nerves  are  in  lateral  relationship  as  they  traverse 
the  cavernous  sinuses.  Above  and  in  front  of  the  pituitary,  and 
in  front  of  the  stalk,  is  situated  the  optic  chiasma. 

The  importance  of  these  relationships  is  evident  when  we  are 
called  upon  to  consider  the  pressure-effects  which  may  be  pro- 
duced by  an  enlarged  pituitary,  or  to  operate  upon  this  organ. 

Vascular  supply  of  the  pituitary.— -This  has  been  studied  by 
Herring1  and  by  Dendy  and  Goetsch2,  and  it  is  chiefly  to  these 
workers  that  we  owe  our  knowledge  of  the  details  concerning  the 
blood-supply  of  this  organ. 

Herring  examined  the  internal  circulations  and  showed  that 
the  main  vessels  of  the  pars  anterior  and  of  the  pars  posterior 
respectively  are  independent  of  one  another.  He  found  that,  if 
the  vessels  be  successfully  injected  with  carmine  gelatine,  the  pars 
anterior  appears  to  be  a  close  network  of  blood-vessels  (fig.  15) — 
previously  known  to  be  the  case  from  histological  investigations 
(fig.  17) — and  that  the  arterial  supply  of  the  pars  anterior  is 
obtained  from  the  internal  carotids  by  means  of  small   arteries 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 

2  Dendy,  W.  E.,  and  E.  Goetsch,  Amer.  Journ.  Anal.,  1911,  xL  137. 


ANATOMY   OF   THE    PITUITARY 


25 


which  reach  their  destination  by  passing  down  the  stalk.  Some 
of  the  veins  from  this  part  of  the  pituitary  run  up  the  stalk 
and  discharge  into  the  large  cavernous  sinuses — designated  the 
'  lateral  sinuses  '  by  Herring — on  either  side  of  the  pituitary ; 
while  other  veins  appear  to  pass  into  the  pars  posterior  (Herring), 
in  which  they  run  beneath  the  pars  intermedia  (fig.  15).  The 
posterior  lobe,  on  the  other  hand,  is  supplied  by  a  median  artery 
which  enters  the  superoposterior  surface  (Gentes1 ;  Herring2). 
This  vessel  arises  from  the  junction  of  two  symmetrical  branches 
from  the  internal  carotid   (Dendy  and  Goetsch).     It  may  be  sug- 


•.Pars  Posterior 


Pars  Nervosa 


Pars  Intermedia 


Fig.  15. 

The  internal  circulation  of  the  pituitary  of  the  cat. 
Herring  of  an  injected  'pituitary. ) 


(After  a  photomicrograph  by 


gested,  therefore,  that  this  artery  be  called  the  azygos  artery  to 
the  pars  posterior  of  the  pituitary. 

The  veins  of  the  pars  posterior  are  situated  beneath  the  cells 
of  the  pars  intermedia,  and  they  unite  to  form  venous  channels, 
most  of  which  pass  out  through  the  superoposterior  surface  in  con- 
junction with  the  azygos  artery,  and  empty  into  the  cavernous 
sinuses,  or  into  the  posterior  communicating  channels. 

It  is  obvious,  then,  that  the  vascular  arrangement  is  some- 


1  Gentes,  L.,  Soc.  Sci.  d'Arcachon  Trav.  des.  laborat,  Bordeaux,  1907,  129. 

2  Herring,  P.  T.,  Journ.  Exper.  Physiol,  1908,  i,  121. 


26  MORPHOLOGY 

what  peculiar.  In  the  pars  anterior  the  small  vessels  are  sinus- 
oidal in  arrangement  and  character  ;  and,  so  far  as  the  arteries 
are  concerned,  they  have  an  origin  different  from  that  of  the 
artery  to  the  posterior  lobe.  On  the  other  hand,  there  is  some 
connexion  between  the  veins  of  the  two  lobes.  This  vascular 
distribution  is  a  matter  of  importance  in  regard  to  the  physio- 
logical interdependence  of  the  two  lobes — a  question  which  will 
be  discussed  at  length  later.  In  general  terms,  the  internal  circu- 
lation of  the  pituitary  may  be  described  as  being  distinctive  in 
regard  to  the  epithelial  portions,  whereas  in  the  pars  nervosa  the 
distribution  of  the  vessels  is  not  very  different  from  that  obtain- 
ing elsewhere  on  the  surface  of  the  brain  in  the  neighbourhood. 

Dendy  and  Goetsch1  studied  especially  the  external  connexions 
of  the  blood-vessels  of  the  pituitary.  They  found  that  the  arterial 
supply  to  the  anterior  lobe  comes  from  a  large  number — often  over 
twenty — small  branches  of  the  internal  carotids  and  the  anterior 
communicating  arteries  of  the  circle  of  Willis,  and  that  these 
arteries  converge  towards  the  stalk  ;  also,  that  many  other  vessels, 
which  arise  from  the  posterior  part  of  the  circle  of  Willis,  pass 
over  the  corpora  mamillaria  to  reach  the  posterior  aspect  of  the 
stalk  (fig.  16),  down  which  run  all  the  arteries  to  the  pars  anterior, 
as  already  described. 

The  venous  channels  from  the  j3ars  anterior  take  a  course  very 
similar  to  that  of  the  arteries  (fig.  16),  and  pass  into  the  circular 
sinus — for  the  most  part  laterally  into  the  cavernous  sinuses ; 
while  the  veins  from  the  pars  posterior  empty,  as  already  men- 
tioned, into  the  posterior  communicating  sinus  or  into  the  caver- 
nous sinuses. 

It  has  been  stated  by  Dendy  and  Goetsch  that  if  a  para- 
hypophysis— which  is  probably  an  accessory  distal  epithelial 
structure — be  present,  it  has  a  blood-supply  entirely  separate 
from  that  of  the  rest  of  the  pars  anterior  :  small  independent 
arteries  reach  this  body  from  the  internal  carotids  on  either  side, 
and,  it  is  said,  a  single  artery,  arising  in  two  trunks  from  the 
ununited  arteries  to  the  pars  posterior  ot  the  pituitary  proper, 
enters  the  posterior  aspect. 

This  singular  arterial  distribution  does  not  correspond  with  the 
view  usually  held  that  this  body  is  an  accessory  pars  anterior  only, 

1  Dendy,  W.  E.,  and  E.  Goetsch,  Amer.  Journ.  Anal,  1911,  xi,  137. 


ANATOMY   OF   THE   PITUITARY 


27 


as  is  almost  certainly  the  case.  The  venous  blood  from  this  struc- 
ture is  said  to  be  carried  away  by  a  single  small  vein  which  enters 
the  floor  of  the  sella  turcica.  If,  then,  the  body  be  an  accessory 
organ — and  almost  certainly  it  is  an  accessory  pars  anterior,  judg- 


Fig.  16. 

Diagram  to  show  the  external  arterial  and  venous  circulation  of  the  pituitary 
seen  from  below,  as  described  by  Dendy  and  Goetsch. 


ing  from  the  structure  of  it  and  its  situation  over  the  site  of  the 
channel  formed  by  the  neck  of  Rathke's  pouch — when  it  is  pre- 
sent the  separate  blood-supply  might  permit  the  removal  of  the 
pituitary  proper,  wholly  or  in  part,  without  the  production  of 
symptoms  ;    for   the    blood-supply  of  the   accessory  organ  being 


28  MORPHOLOGY 

uninjured,  this  structure  might  take  on  the  functions  of  the  parts 
removed. 

Nervous  connexions  with  the  pituitary. — These  are  related 
to  the  sympathetic  system.  The  evidence  concerning  their  pre- 
sence in  the  pituitary  is  histological,  and  will,  therefore,  be  dis- 
cussed more  fully  presently. 


HISTOLOGICAL    ANATOMY 

The  finer  details  in  the  anatomy  of  an  organ,  such  as 
the  pituitary,  are  closely  related  to  its  functional  energies  ; 
consequently  only  a  brief  account  of  the  histology  of  the  epithelial 
cells  will  be  given  here.  The  significance  of  the  histological 
appearances  of  the  secretory  elements  will  be  discussed  in  con- 
nexion with  the  physiological  aspect  of  the  subject  (p.  82).  It 
has  been  mentioned  that  in  the  mammalian  pituitary  there  are 
three  easily  recognizable  parts — the  distal  epithelium,  the  juxta- 
neural  epithelium,  and  the  pars  nervosa — and  that  the  last  two 
together  form  the  pars  posterior. 

Pars  anterior  (distal  epithelium)  is  composed  of  well- 
defined  epithelial  cells  supported  by  a  framework  of  fine,  but 
tough,  connective  tissue,  and  separated  into  groups  by  large 
blood-vessels  and  sinuses  whose  walls  are  lined  with  a  single  layer 
of  endothelium  (fig.  17). 

Hannover1  in  1844  first  called  attention  to  the  occurrence  of 
more  than  one  type  of  cell  in  the  pars  anterior  of  the  frog  and 
Man.  He  found  that  the  same  structure  in  the  fowl  consists 
almost  exclusively  of  one  variety  of  small  cells.  No  further 
observations  of  importance  appear  to  have  been  made  until  the 
year  1884,  when  Flesch2  and  Dostoiewsky3,  working  independ- 
ently, described  cells  of  two  different  types — the  chromophil  and 
chromophobe.  To  Lothringer4,  however,  is  due  the  credit  of 
showing  definitely  the  staining  affinities  of  these  dissimilar  cells. 

1  Hannover,  A.,  Eecherches  Microscopiques  sur  le  System  Nerveux,  1844,  26. 

2  Flesch,  M.,  Tageblatt  der  57  Versammlung  Deutscher.  Nafurforscher  und  Aerzfe 
zu  Magdeburg,  1884,  195.      (Quoted  by  Dostoiewsky.) 

3  Dostoiewsky,  A.,  Arch.  f.  Mikr.  Anal,  1886,  xxvi,  592. 

4  Lothringer,  S.,  Arch.  f.  Mikr.  Anat.,  1886,  xxviii,  257. 


ANATOMY   OF   THE   PITUITARY  29 

Many  subsequent  workers,  among  whom  Rogowitsch1,  Steida2, 
Pisenti  and  Viola3,  Schonemann4  and  Launois5  were  the  most 
prominent,  have  confirmed  and  extended  these  observations. 

Three  varieties  of  epithelial  cells  are  found  in  the  pars  anterior. 
Whether  these  cells  are  distinct  varieties  or  only  the  same  type 
of  cell  in  different  stages  of  functional  activity  will  be  discussed 
later.  At  the  moment  we  are  only  concerned  with  the  general 
histological  appearances. 

•         o     .      «  •  e  g     *e    %  %  -      <g  |   f 

C  *  e°*  ■     @    °o       V  •     %   ?• 

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Fig.   17. 

Section  of  the  normal  human  pars  anterior,  showing  large  blood-sinuses. 

X250. 

Two  of  these  types  are  chromophil  in  their  affinity  for  stains, 
and  of  these,  one  is  acidophil  (eosinophil),  and  the  other  basophil 
(haematoxylinophil)  ;  and  the  third  is  neutrophil  or  chromophobe 
— that  is  to  say,  the  cells  stain  very  faintly  with  basic  dyes.     In 

1  Rogowitsch,  X.,  Zeigler's  Beitr.  z.  Pathol.  Anat.  u.  z.  Ally.  Pathol.,  1889, 
iv,  453. 

2  Stieda,  H.,  Zeigler's  Beitr.  z.  Pathol.  Anat.  u.  z.  Allg.  Pathol.,  1890,  vii,  537. 

3  Pisenti,  G.,  and  G.  Viola,  Centralbl.  f.  die  Med.  Wissensch.,  1890,  xxviii,  450. 

4  Schonemann,  A.,  Virchow's  Archie,  1892,  129,  310. 

6  Launois,  P.  E.,  La  glatide  hypophysaire  de  Vhomme,  1904. 


30  MORPHOLOGY 

consequence  of  these  differences  and  degrees  of  affinity  for  staining 
agents,  the  normal  human  pituitary  presents  an  easily  recognizable 
appearance  when  examined  in  section  under  the  microscope 
(plate  1)  :  large  brightly  stained  pink  cells  (eosinophils)  are  mixed 
— -apparently  indiscriminately — with  big  darkly  stained  blue  cells 
(basophils),  and  small  lightly  stained  grey-blue  or  faintly  pink- 
blue  cells  (chromophobes). 

In  normal  circumstances  in  the  human  subject  the  eosinophils, 
which  are  finely  or  coarsely  granular,  and  have  a  centrally  placed 

,     1       i      'J  '  e      a   '3      t  ■■  °°    '.     o  &*  p    c 


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Fig.  18. 

Section  of  the  normal  human  pars  anterior,  showing  acinous  arrangement  of 
eosinophil  cells  with  granular  secretion.  A  small  group  of  basophils  is  seen  in  the 
upper  part  of  the  field. 

X250. 

nucleus,  predominate ;  but  numerous  basophils,  both  coarsely 
granular  and  homogeneous,  with  eccentrically  placed  nuclei,  may 
be  seen,  especially  at  the  periphery.  Usually,  chromophobe 
(neutrophil)  cells  are  infrequent,  although  the  cells  of  the  pars 
anterior  that  abut  on  the  cleft  may  tend  to  be  chromophobe. 
In  this  situation  the  cells  are  well  formed,  and  have  definite 
outlines  and  small  nuclei ;  but  those  found  in  the  rest  of  the 
pars  anterior  are  small  and    sparsely  granular,  and  have  large. 


[Facing  page  50. 


*     e 


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PLATE    1. 

Section  of  the  normal  pars  anterior  in  the  human  subject,  showing 
basophil,  eosinophil  and  neutrophil  cells. 

X  500 

(Direct  colour  photomicrograph). 


Facing  page  31], 


S 


PLATE   2. 

Section  of  the  normal  pars  anterior  in  the  human  subject,  showing 
a  large  mass  of  basophil  colloid  surrounded  by  neutrophil  and  faintly 
eosinophil  cells. 

X  500 

(Direct  colour  photomicrograph ) . 


ANATOMY   OF   THE   PITUITARY  31 

clear,  centrally  placed  nuclei  with  prominent  chromatin  fibres. 
As  we  shall  see  later,  these  appearances  vary  considerably  in 
different  animals,  and  in  certain  physiological  and  pathological 
states. 

It  is  not  at  all  uncommon  to  find  the  eosinophil  cells  in  the 
pars  anterior  arranged  in  a  tubular  or  vesicular  manner,  with 
masses  of  granular — not  colloid — secretion  in  the  centre  (fig.  18). 
Occasionally,  numbers  of  basophils  are  seen  collected  together  in 
a  somewhat  similar  acinous  disposition  (fig.   19).      Nevertheless, 

"•  ,^    ,  c     :  ,  3/»    *  :..-- 

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e 


5> 


C>  a*,    "  .  -  Z- 

'  '        G  1     :  >  ■  < 


ft 


c    n 


-> 


Fig.  19. 

Section  of  the  normal  human  pars  anterior,  showing  groups  of  basophil  cells. 

X300. 

as  will  be  explained  in  discussing  the  physiological  significance 
of  these  cells,  such  well-marked  basophils  do  not  surround 
masses  of  secretion,  although  sometimes  a  dark  homogeneous 
basophil  cell  is  seen  in  the  wall  of  a  vesicle  surrounding  baso- 
phil colloid  (plate  2) :  for  the  most  part  the  cells  surrounding 
this  substance  are  chromophobe  or  lightly  eosinophil.  Colloid 
material  is,  too,  sometimes  seen  in  the  blood-vessels  and  sinuses 
(Thaon). 

Many  investigators    have  described  nerve-fibres  and  cells  in 


32 


MORPHOLOGY 


the  pars  anterior,  but  Berkley1  was  the  first  to  give  a  complete 
and  accurate  account  of  the  distribution  of  the  nervous  elements. 
This  investigator  found  that  only  sympathetic  nerve-fibres  from  the 
carotid  plexus  are  present,  and  that  there  are  no  true  nerve-cells 
or  fibres  in  this  part  of  the  pituitary.  These  sympathetic  fibres, 
which  are  very  fine  and  varicose,  come  off  the  main  stem  approxi- 
mately at  a  right  angle,  cross  the  sinuses  to  run  an  irregular 
course    among    the    epithelial    cells,   and    finally  break    up    into 


Fig.  20. 

Section  of  the  normal  human  pars  anterior,  showing  sympathetic  nerve  fibres. 
{Partly  plwtomicrographic.) 

X300. 

branching  terminations  with  numerous  ball-shaped  endings  which 
lie  in  the  intercellular  tissue  (fig.  20). 

Thaon2  states  that  he  has  investigated  the  matter  carefully 
and  has  failed  to  find  any  lymphatics  Avhatsoever  in  the  pars 
anterior.     Caselli3,  however,  asserts  that  lymphatics  are  abundant, 


1  Berkley,  H.  J.,  Brain,  1894,  xvii,  515. 

2  Thaon,  P.,  Uhypophyse,  Paris,  1907. 

3  Caselli,  A.,  Studi   Anat.   e  Sperhnent.    Fisiopatologia  d.   Olandola  Pituitaria. 
Rea-gio  nell'  Emilia.  1900. 


ANATOMY   OF  THE   PITUITARY  33 

while  Pisenti  and  Viola1  and  Herring2  state  that  there  is  con- 
siderable doubt  as  to  whether  they  exist  or  not.  Edinger3 
believes  that  lymph-spaces  separate  the  epithelial  cells  from  the 
blood-sinuses.  Most  observers,  however,  agree  that  lymphatics, 
if  present,  must  be  extremely  few  in  number. 

Pars  intermedia  {juxtaneural  epithelium).  This  portion  of 
the  pituitary  body  was  first  identified  and  described  by  Pere- 
meschko4.  As  we  have  seen,  the  juxtaneural  epithelium  is  differ- 
entiated from  the  distal  epithelium  (pars  anterior)  in  the  process 
of  development.  It  is  for  the  most  part  applied  to  the  surface 
of  the  pars  nervosa,  which  abuts  on  the  cleft,  and  to  the  region 
of  the  neck  ;  but  the  extent  and  distribution  of  the  juxtaneural 
epithelium  varies  enormously  in  different  animals.  In  some,  such 
as  the  cat  and  dog,  the  distribution  is  very  extensive  :  not  only 
is  the  epithelium  applied  to  the  surface  of  the  pars  nervosa, 
completely  enclosing  it,  and  collected  in  a  large  mass  around  the 
neck,  but  it  extends,  also,  in  a  tongue-shaped  projection  along  the 
base  of  the  brain  above  the  pars  anterior  (figs.  47  and  51).  In 
these  animals,  too,  the  cells  in  the  neighbourhood  of  the  neck  and 
above  the  pars  anterior  are  arranged  in  the  form  of  vesicles,  which 
enclose  much  granular  secretion  (figs.  48  and  52).  In  the  human 
pituitary  colloidal  secretion  is  sometimes  found  in  the  pars  inter- 
media above  the  cleft,  and  also  in  the  cleft  itself.  This  secretion 
in  the  pars  intermedia  and  cleft  of  the  human  pituitary  is  most 
frequently  seen  in  the  female  during  and  just  after  pregnancy, 
and  in  old  age  in  both  sexes.  The  juxtaneural  epithelium, 
however,  in  the  human  subject  is  very  scanty  and  forms  a 
thin  layer  covering  the  pars  nervosa  where  it  adjoins  a  very 
narrow  cleft  (fig.  21).  At  the  upper  limit  of  the  cleft  and 
around  the  stalk  the  cells  are  more  numerous,  but  never  occur 
in  large  numbers. 

The  juxtaneural  epithelium  is  usually  faintly  basophil,  or 
neutrophil,  in  its  staining  reactions.  The  cells  are  finely  granular 
and  polygonal  in  shape.  In  those  animals,  such  as  the  cat,  in 
which  there  are  many  layers  of  epithelium  lining  the  cleft,  the 

1  Pisenti,  G.,  and  G.  Viola,  Centralbl.  f.  die  Med.  Wissensch..  1890,  xxviii,  450. 

2  Herring,  P.  T.,  Quart.  Joum.  Exper.  Physiol,  1908.  i,  121. 

3  Edinger,  L.,  Archiv.  f.  Mikr.  Anal,  1911,  lxxviii,  496. 

4  Pereraeschko  (no  initial  in  the  original),  Virchow's  Archiv.,  1867,  xxxviii,  329. 

3 


34  MORPHOLOGY 

distribution  is  unequal;  consequently  projections  of  wedge-shaped 
epithelial  masses  are  frequently  seen  dipping  down  into  the  pars 
nervosa.  In  these  circumstances,  also,  the  epithelial  elements 
lining  the  cleft  are  often  flattened  on  the  free  surface  and  are 
triangular  in  shape,  with  an  angle  dipping  down  into  the  cells 
beneath  ;  and  the  cells  which  are  in  contact  with  the  pars  nervosa 
may,  also,  resemble  in  shape  the  foot-cells  of  the  testicle.  In 
many  animals— but  never  in  man — supporting  spindle-shaped  cells 


£ 


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Fig.  21. 

Section  of  the  normal  human  pituitary,  showing  the  pars  intermedia  above  and 
abutting  on  the  cleft. 

X250. 

arranged  vertically  to  the  surface  are  seen  among  the  epithelial 
elements,  covering  the  pars  nervosa  ;  sometimes,  as  in  the  lemur, 
there  is  a  considerable  amount  of  connective  tissue,  in  connexion 
with  which  there  may  be  blood-vessels,  dividing  the  cells  into 
groups. 

At  the  junction  of  the  pars  intermedia  and  the  pars  anterior 
there  is  often  an  almost  insensible  gradation  from  one  to  the 
other.  In  these  circumstances  the  line  of  junction  only  can  be 
identified    by   the    difference    in   the   staining   reactions,    by   the 


ANATOMY   OF   THE    PITUITARY  35 

shape  and  size  of  the  cells,  and  by  the  assumption  of  a  vesicular 
arrangement  in  the  pars  intermedia  different  from  that  found 
in  the  pars  anterior. 

As  we  have  seen,  usually  no  blood-vessels  or  lymphatics  are 
found  in  the  juxtaneural  epithelium  lining  the  cleft,  but  many 
large  blood-vessels  and  much  supporting  connective  tissue  are 
found  among  the  vesicles  above  the  pars  anterior  and  around  the 
neck  in  those  animals  in  which  this  arrangement  is  well  defined 
(fig.  49).  Lymphatics,  also,  according  to  Herring1,  are  to  be  found 
in  this  region.  Thaon2,  on  the  other  hand,  denies  the  presence 
of  lymphatic  vessels. 

The  nervous  elements  of  the  pars  intermedia  will  be  discussed 
in  connexion  with  the  pars  nervosa. 

Pars  nervosa  is  chiefly  composed  of  neuroglial  cells  and 
fibres  (fig.  22),  but  there  is  a  small  amount  of  connective  tissue, 
and  Thaon2  has  observed  collagen-fibres.  In  some  animals  there 
is  a  central  cavity  communicating  with  the  third  ventricle,  and 
lined  with  ependyma-cells  ;  but  in  man  and  most  mammals  this 
portion  of  the  pituitary  is  solid. 

In  certain  circumstances  large  cells  of  the  pars  intermedia 
may  be  found  in  the  pars  nervosa,  and  even  large  masses  of 
neutrophil  granular  secretion  derived  from  these  cells  or  from 
the  pars  intermedia  directly.  The  importance  of  these  cellular 
and  secretory  incursions  will  be  discussed  later  in  connexion 
with  their  functional  significance. 

The  configuration  and  distribution  of  the  neuroglia-cells  and 
their  fibres  have  been  depicted  by  many  writers  ;  and  Berkley3, 
Osborne  and  Vincent4,  and  other  observers  have  described  the 
presence  of  true  nerve-cells  and  nerve-fibres  in  this  part  of  the 
pituitary.  Berkley,  if  I  understand  him  correctly,  also  states 
that  the  epithelial  cells  of  the  pars  intermedia  abutting  on  the 
cleft  are  enclosed  in  a  capsule  of  ependyma-cells  which  send 
long  processes  down  among  the  epithelial  elements.  This  ob- 
servation has  not  been  confirmed — indeed,  on  developmental 
grounds  such  a  phenomenon  is  incapable  of  belief. 

1  Herring,  P.  T.,  Qxvart.  Journ.  Exper.  Physiol.,  1908,  i,  121. 

2  Thaon,  P.,  L'hypophyse,  Paris,  1907. 

3  Berkley,  H.  J.,  Brain,  1894,  xvii,  515. 

4  Osborne,  W.  A.,  and  S.  Vincent,  Brit.  Med.  Journ...  1900,  i,  502. 


36 


MORPHOLOGY 


Many  types  of  neuroglial  cells  are  to  be  found,  and  these 
varieties  relate  chiefly  to  the  profusion  or  otherwise  of  the 
processes  arising  from  them. 

According  to  Berkley  the  true  nerve-cells  are  situated  chiefly 
in  the  lower  and  anterior  part  of  the  pars  nervosa.  This  author 
has  divided  them  into  two  groups — those  having  one  dendrite 
and  those  having  more  than  one.  Caselli1,  Herring2,  and  most 
other  observers  deny  the  existence  of  true  nerve-cells  in  the 
pars  posterior.      They  believe  that  the  nervous  elements  consist 


Fig.  22. 
Neuroglial  cells  and  fibres  in  the  pars  nervosa  of  the  cat.     (After  Herring.) 

entirely  of  neuroglial  and  ependymal  tissues.  With  regard 
to  the  ependymal  cells,  these  are  found  in  the  neighbourhood 
of  the  neck,  and  sometimes  as  inclusions  in  the  centre  of  the 
pars  nervosa  in  those  animals  in  which  the  central  cavity  has 
been  obliterated  in  the  process   of  development. 

No  evidence  has  yet  been  adduced  to  show  that  the  sympath- 
etic nerves   leave  the  blood-vessels   in   the   pars   nervosa    as   in 

1  Caselli,  A.,  Studi  Anat.  Sperimerd.  Fisiopatologia  d.  Glandola  Pituitaria,  Reggio 
nell"  Emilia,  1900. 

2  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 


ANATOMY    OF   THE   PITUITARY  37 

the  case  of  the  pars  anterior.  It  has  been  suggested,  however, 
that  such  fibres  may  possibly  reach  the  pars  intermedia  from 
the  pars  anterior.  The  internal  blood-supply  of  the  pars  post- 
erior has  already  been  described  (p.  24). 

Special  attention  has  been  directed  by  Kohn1  and  others 
to  a  peculiar  pigment  which  has  long  been  known  to  exist 
in  the  neuroglial  fibres  of  the  pars  nervosa.  Fischer2  con- 
siders that  this  substance  is  the  result  of  degeneration  in 
old  age. 

The  composition  and  origin  of  this  pigment  has  not  been 
discovered,  but  according  to  Biedl3,  it  has  been  shown  to  be 
neither  a  fat  nor  a  lipochrome. 

Clunet  and  Jonnesco4,  also,  have  made  a  careful  study  of 
this  material.  They  have  found  that  it  is  possible  with  the 
naked  eye  to  observe  the  pigment  in  unstained  sections  held  up 
to  the  light  :  it  is  chiefly  seen  in  the  posterior  part  of  the 
pars  nervosa,  although  it  may  be  distributed  throughout.  The 
granules  are  more  or  less  spherical,  and  are  brownish-yellow  or 
greenish  in  colour. 

It  was  found  by  these  investigators  that  neither  hydrochloric 
acid  nor  acetic  acid  has  any  effect  on  the  pigment,  but  that 
sulphuric  acid  turns  it  black  without  dissolving  it.  It  is  in- 
soluble in  alcohol,  xylol,  benzene,  chloroform,  ether,  and  cedar- 
wood  oil.  Strong  solutions  of  ammonia  and  of  caustic  potash 
and  soda  will  only  affect  this  substance  after  prolonged  contact 
— that  is  to  say,  after  twenty-four  or  more  hours — when  it  may 
be  completely  dissolved. 

The  pigment  does  not  give  the  iron  reactions.  It  is  not 
turned  brown  by  osmic  acid,  nor  coloured  red  by  sudan  III  and 
scharlack  R  ;  and  it  is  not  stained  by  hematoxylin,  haematin, 
or  safranin,  but  it  is  changed  to  an  intense  black  by  iron- 
hsematoxylin,  and  blue  by  Giemsa's  stain.  It  is  tinted,  also,  by 
a  few  of  the  rarer  dyes. 

Livon    and    Peyron5   have    discussed    the    importance  of  this 

1  Kohn,  A.,  Archiv.  f.  Mihr.  Aaat.,  1910,  lxxv,  337. 

2  Fischer,  B.,  Hypophysis,  Akromegalip  mul  Fiilsucht,  Wiesbaden,  1910. 

3  Biedl,  A.,  Inner e  Sekretion,  2nd  ed.,  1913. 

4  Clunet,  J.,  and  V.  Jonnesco,  Compt.  Rend.  Soc,  Biol.,  1910,  lxix,  020. 

5  Livon,  C,  and  Peyron  (no  initial  in  the  original),  Compt.  Rend.  Soc,  Biol,  1911, 
Ixx.  730. 


38  MORPHOLOGY 

substance  in  a  somewhat  vague  communication.  These  authors 
look  upon  the  pigment  as  a  product  elaborated  by  the  neuroglial 
elements  from  the  secretion  of  the  glandular  portion  of  the 
pituitary  ;  but  whether  this  is  effected  by  a  process  of  assimila- 
tion or  deposition  they  were  unable  to  discover. 

Histological  appearances  of  the  pituitary  at  different 
periods  of  life. — Very  few  observers  have  published  accounts 
of  the  histological  appearances  of  the  pituitary  at  different 
periods  of  life,  although  many  writers  have  assumed  that  dif- 
ferences exist  at  various  ages.  Our  own  somewhat  scanty 
observations  agree  with  the  findings  of  Thaon1. 

In  early  childhood  the  pars  anterior  appears  to  be  inactive. 
The  epithelial  cells  are  small  and  closely  packed ;  they  show 
very  little  evidence  of  differential  staining,  and  the  blood-sinuses 
contain  but  little  blood.  The  cells  of  the  pars  intermedia,  also, 
are  shrunken  in  appearance,  and  colloid  is  never  seen  in  this 
region,  but  small  masses  of  granular  secretion  may  be  found  in 
the  pars  anterior. 

About  puberty  functional  development  is  to  be  observed  :  the 
epithelial  cells  become  large,  and  show  faintly  differential  stain- 
ing. After  this  period  the  cells  gradually  come  to  resemble  the 
ordinary  adult  types,  the  blood-sinuses  become  distended  and 
the  whole  organ  shows  normal  activity. 

In  old  age  the  pituitary  is  very  little  different  in  appearance 
from  the  adult  organ  :  the  epithelial  elements  are  active  and 
stain  well.  It  is,  however,  certainly  more  usual  to  see  masses 
of  colloid  in  the  cleft  and  in  the  vesicles  of  the  pars  intermedia 
than  is  usual  in  middle  life  apart  from  pregnancy.  But  there  is 
no  evidence  of  senile  atrophy  as  described  by  Caselli2 ;  although, 
pathologically,  sclerotic  changes  in  the  pituitary  may  be  observed 
in  association  with  similar  lesions  elsewhere. 

Fischer3,  as  already  stated,  describes  the  deposit  of  pigment 
in  the  neuroglial  fibres  as  an  old-age  change. 

Geurrini4  examined  young  guinea-pigs  and  rabbits,  and  found 

1  Thaon,  P.,  Uhypophyse,  Paris,  1907. 

2  Caselli,  A.,  Studi  Anat.  e  Speriment.  Fisiopatologia  d.  Qlandola  Pituitaria,  Reggio 
neir  Emilia,  1900. 

3  Fischer,  B.,  Hypophysis,  Akromegalie  und  Fettsucht,  Wiesbaden,  1910, 

4  Guerrini,  G.,  Arch.  Ital.  de  Biol,  1905,  xliii,  1. 


ANATOMY   OF   THE   PITUITARY  39 

that  so  long  as  they  were  suckled  the  pituitary  presented  an 
inactive  appearance,  but  that  activity  became  evident  as  soon 
as  they  were  weaned.  Thaon1,  however,  could  find  no  such 
differences  between  the  pituitaries  of  lambs  and  older  sheep. 

1  Thaon,  P.,  Uhypophyse,  Paris,  1907. 


§iii.     COMPARATIVE   ANATOMY   OF   THE   PITUITARY 

Since  most  of  the  histological  and  physiological  investigations 
in  regard  to  the  pituitary  have  been  carried  out  in  connexion 
with  the  organs  obtained  from  the  lower  animals,  we  are  in 
possession  of  a  considerable  amount  of  information  concerning 
the  comparative  features  of  this  organ  in  the  commoner  mammals, 
such  as  the  cat,  dog  and  rabbit ;  but  more  primitive  mammals 
and  the  lower  vertebrata  have  not  been  investigated  quite  so 
completely. 

Nevertheless,  thanks  to  the  researches  of  Andriezen1,  Haller2, 
Sterzi3,  Gentes4,  Herring5,  Tilney6,  and  a  few  others,  we  have 
some  certain  knowledge  concerning  the  pituitaries  of  the  lowest 
vertebrates — the  commoner  fishes,  amphibians,  reptiles  and 
birds. 

The  importance  of  such  comparative  studies  is  very  great, 
not  only  from  a  morphological  point  of  view,  but  also  from  a 
physiological. 

CYCLOSTOMATA 

Petromyzontes. — Andriezen1,  so  far  as  I  can  discover  from 
his  paper  which  is  somewhat  obscure  and  involved,  claims  to 
have  shown  by  an  investigation  of  ammoccetes — the  larval  stage 
of  petromyzon  planeri — that   the    primitive   pituitary,    which   he 

1  Andriezen,  W.  L.,  Brit.  Med.  Journ.,  1894,  i,  54. 

2  Haller,  B.,  Morphol  Jahr.,  1896,  xxv,  31. 

3  Sterzi,  A.  (quoted  by  Gentes4),  Atti  deWAcad.  Sci.  Vencto-Trentino-Isfriana, 
1904,  i,  72. 

4  Gentes,  L.,  Soc.  Sci.  d'Arcachon,  Travaux  des  laborat.,  Bordeaux,  1907,  129. 

5  Herring,  P.  T.,  Qvart.  Journ.  Exper.  Physiol.,  1908,  i.  121  ;  idem,  1908,  i,  261  ; 
idem,  1913,  vi,  73. 

6  Tilney,  F.,  Memoirs  Wistar  Inslit.  Anal,  and  Biol,  Philadelphia,  1911 
(No.  2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY    41 

describes  as  being  composed  of  three  parts,  is  a  water- vascular 
organ.  There  is,  he  says,  a  median  subneural  glandular  organ 
arising  from  the  buccal  epithelium,  a  duct  lined  with  ciliated 
epithelium  connecting  the  buccal  and  neural  cavities,  and  a  group 
of  nerve-cells  closely  investing  the  upper  (neural)  opening  of  the 
duct.  From  these  observations  he  draws  the  following  conclu- 
sions. First,  the  open  duct  implies  the  presence  of  a  water- 
vascular  system — a  system  whereby  water  is  admitted  from  the 
buccal  cavity  to  the  neural  canal,  in  order  that  oxygen  may  be 
conveyed  to  the  nervous  elements  and  waste  products  removed 
by  way  of  the  posterior  aperture.  Second,  the  glandular  organ 
pours  its  secretion  into  the  neurobuccal  duct,  wherein  it  is 
carried  by  the  water-stream  into  the  neural  canal.  Third,  the 
duct  and  attached  sensory  (selective)  nervous  elements  are  only 
functional  in  very  primitive  vertebrates,  and  atrophy  in  the 
higher  ;  and  in  the  latter  the  glandular  portion  which  persists 
secretes  into  lymphatics,  and  thence  into  the  blood-stream. 

Sterzi1  and  Gentes2  have  examined  the  fully  developed 
petromyzon  fluviatilis,  and  have  given  a  very  complete  descrip- 
tion of  the  pituitary  in  this  creature. 

According  to  Gentes,  the  hollow  infundibular  process  extends 
downwards  into  the  narrower  recessus  hypophyseus,  the  wall  of 
which  forms  the  lobus  infundibuli.  Below  and  around  the  con- 
vexity of  this  lobe  is  the  juxtaneural  epithelium.  This  is 
separated  from  the  infundibular  process  by  connective  tissue  and 
vessels.  Gentes  refers  to  this  epithelial  layer  as  the  '  posterior 
lobe  '  ;  and  he  divides  the  distal  epithelial  portion  into  two  lobes 
— an  anterior  and  a  middle  (fig.  23) — which  are  separated  from 
one  another  by  connective  tissue,  as  is  the  middle  lobe  from 
the  '  posterior '.  Sterzi  first  noted  that  the  middle  lobe  is 
chromophobe  in  its  reaction  to  the  usual  stains,  while  the 
anterior  and  '  posterior  '  lobes  are  chromophil.  The  chromophil 
cells  appear  to  be  of  one  character  only  and  stain  best 
with  iron-haematoxylin.  The  middle  lobe  is  approximately  of 
the  same  size  as  the  anterior. 

Herring3,   also,   has  examined  the  pituitary  of   the  lamprey, 

1  Sterzi,  A.  (quoted  by  Gentes  2),  Atti  dell'  Accad.  Sci.  Veneto-Trenii no-Istrla no, 
1904,  i,  72. 

2  Gentes,  L.,  Soc.  Sci.  d'Arcachon,  Travaux  des  laborat.,  Bordeaux,  1907,  129. 

3  Herring.  P.  T.,  Quart.  Joum.  Exper.  Physiol.,  1913,  vi,  73. 


42 


MORPHOLOGY 


and   his   description   agrees  in  all  essentials  with  that  given  by 
Gentes. 

Tilney1  states  that  the  pituitary  in  this  vertebrate  is  recog- 
nizably representative  of  that  found  in  the  higher  vertebrates, 
although  he  noted  certain  peculiar  features.  There  is,  he  states, 
a  definite  pars  anterior  (distal  epithelial  portion),  but  the  cells 
are  arranged  in  parallel  columns  set  perpendicularly  to  the  base 
of  the  brain.     These  cells  stain  indifferently  with  hematoxylin. 


Fig.  23. 

<—  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  lamprey  (pctromyzon  Jluviatilis). 
(After  Genles.)  I,  infundibular  process  (3rd  ventricle);  H,  infundibular  recess; 
PN,  pars  nervosa ;  JN,  juxtaneural  epithelium ;  ADN,  chromophil  portion  of 
distal  epithelium  ;  BDN,  chromophobe  portion  of  distal  epithelium ;  C,  cavity ; 
NP,  nasopharangeal  canal. 

The  cells  of  pars  intermedia  (juxtaneural  epithelium)  are 
arranged  in  convoluted  cords,  they  stain  deeply  with  haema- 
toxylin,  and  are  attached  to  a  short  but  distinct  infundibular 
process.  Tilney  could  find  no  evidence  of  a  residual  cleft,  nor 
did  he  discover  colloid  material  or  supporting  connective  tissue 
among  the  epthelial  cells. 

1  Tilney,  F.,  Memoirs  Wisiar  Instil.  Anal.  &  Biol.,  Philadelphia,  1911 
(No.   2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     43 


PISCES 

Elasmobranchii. — According  to  both  Gentes1  and  Herring2, 
in  these  primitive  fishes  the  pituitary  is  represented  practically 
entirely  by  an  organ  of  a  glandular  character  (distal  epithelium). 

Gentes1  states  that  there  is  no  posterior  lobe  in  elasmo- 
branchs  ;  but  Herring  found  that  in  the  skate  there  is  a  "  thin 
lamina  of  nervous  tissue  which  bounds  the  infundibular  cavity 
and  passes  into  the  tissue  of  the  pituitary",  but  that  this  is  the 
"  nearest  approach  to  anything  resembling  a  posterior  lobe".  It 
may  be  assumed,  therefore,  that,  even  if  the  pars  nervosa  be 
present  in  the  restricted  sense  described  by  Herring,  it  is  prob- 


Fio.  24 

<—  Anterior  direction. 

Median  sagittal  section  of  the  pituitary-  of  the  skate  (raid  batis).  {After 
Herring.)  A,  distal  epithelium  enclosing  cavity  ;  B,  main  part  of  distal  epithelium  ; 
C,  infundibular  cavity;  O,  optic  chiasma. 

ably  quite  functionless  in  these  creatures  ;  indeed,  Herring2  has 
shown  that  no  physiologically  active  pressor  extract  can  be  made 
from  the  pituitary  of  elasmobranchs,  although  such  a  product  is 
easily  obtainable  from  the  pituitaries  of  the  higher  vertebrates. 
In  the  skate  {rata  batis)  the  pituitary  forms  an  elongated 
body  :  the  anterior  portion  extends  forwards  like  a  tongue,  while 
posteriorly  the  organ  is  oval  in  shape  (fig.  24).  In  the  centre  of 
the  anterior  prolongation  of  the  glandular  tissue  there  is  a 
ventricle,  or  canal  ;  and  the  hollow  infundibular  process  is  in 
close  proximity  to  the  upper  surface  of  this  glandular  structure. 

1  Gentes,  L.,  Soc.  Sci.  d'Arcachon,  Travaux  des  laborat.,  Bordeaux,  1907,  12'.). 

2  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol.,  1908,  vol.  i,  p  261  ;  idem,  1913, 
vi,  73. 


44 


MORPHOLOGY 


On  histological  examination  the  organ  is  found  to  be  made  up 
of  what  at  first  sight  appear  to  be  acini — closely  resembling, 
indeed,  the  acini  seen  in  the  fcetal  pituitary  of  the  higher 
mammals  (see  fig.  10,  p.  13);  but,  as  Gentes  has  pointed 
out  in  the  case  of  torpedo  marmorata,  the  central  lumina  are 
blood-channels  ('capillaire  sanguin  sinusoidal'1)  surrounded  by 
glandular  cells  (fig.  25).  This  observation,  which  has  been 
confirmed    by    Herring,    is    of    considerable    importance,    for    it 


Fig.  25. 

Section  of  the  distal  epithelial  portion  of  the  pituitary  of  the  skate  (raia  batis), 
showing  the  glandular  arrangement  of  columnar  cells  around  blood-channels  lined 
with  endothelium.     {After  Herring.) 


demonstrates  clearly  that  in  the  primitive  state  the  pituitary, 
which  consists  only  of  a  glandular  structure  surrounding  sinuses, 
secretes  directly  into  the  blood-stream.  In  the  elasmobranchs 
there  is  no  differentiation  in  the  staining  reactions  of  the 
secretory  cells.  According  to  Herring,  no  chromophil  elements 
are  to  be  seen.  The  cells  are  columnar  in  shape  with  basal 
nuclei  and  clear  free  surfaces — in  fact,  typical  secreting  cells. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     45 

Tilney1  states  that  in  the  dog-fish  (squalns  acanthias)  the 
infundibular  process  is  well  developed,  but  is  situated  anteriorly. 

Before  continuing  further  the  study  of  the  comparative 
anatomy  of  the  pituitary  reference  must  be  made  to  a  peculiar 
structure  found  in  relation  to  the  pituitary,  which  is  more  or 
less  well  developed  in  nearly  all  vertebrates  below  the  mammals, 
and  is  known  as  the  '  saccus  vasculosis  '. 

This  structure  is  very  prominent  in  elasmobranchs  and  in 
many  teleosts,  although  according  to  Gentes2  it  is  rudimentary 
or  absent  in  some  of  the  higher  fishes.  Herring3  states  that  the 
saccus  vasculosus  is  bilobed  and  bilateral  in  the  skate  (elasmo- 
branch),  and  single  and  central  in  the  cod  (teleost). 

The  structure  of  the  saccus  vasculosus  is  simple  :  it  consists 
of  a  thin-walled  sac  or  sacs,  lined  with  columnar  epithelium  and 
supplied  by  numerous  blood-vessels.  The  saccus  vasculosus 
opens  by  a  wide  orifice,  or  by  several  orifices,  into  the  cavity 
of  the  infundibular  process ;  consequently  Gentes2  believes  that 
it  is  analogous  to  the  choroid  plexus,  and  that  it  secretes  cere- 
brospinal fluid. 

The  saccus  vasculosus,  from  its  intimate  relationship  to  the 
pituitary,  may  in  the  lower  vertebrates  give  rise  to  difficulty  in 
the  interpretation  of  the  histological  appearances  of  that  organ 
unless  the  propinquity  of  the  two  structures  be  fully  recognized. 
In  the  skate  the  saccus  vasculosus  is  bilobed  and  bilateral  in 
position  ;  consequently  it  is  not  seen  in  mesial  sections. 

Teleostei. — In  the  bony  fishes  definite  differentiation  of  the 
various  parts  of  the  pituitary  is  seen,  but  in  the  diverse  species 
the  relation  of  these  parts  to  one  another  varies. 

In  the  cod  (gadus  morrhua),  which  is  described  by  Herring4, 
the  chromophil  cells,  which  may  be  considered  representative 
of  the  pars  anterior  proper  of  mammals,  are  found  in  a  compact 
mass  sandwiched  between  neutrophil  cells  (fig.  26).  The  two 
groups  of  neutrophil  cells  are  in  close  relationship  with  nervous 

1  Tilney,   F.,   Memoirs    Wistar    Instil    Anal    and    Biol.,    Philadelphia,    1911 
(No.  2),  1. 

2  Gentes,  L.,  Soc.  Sci.  cVArcachon,  Travaux  des  laboral,  Bordeaux,  1907,  129. 

3  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  211  -,  idem,  1913,  vi,  73. 

4  Herring,  P.  T.    Quart.  Journ.  Exper.  Physiol,  1908,  i,  261  ;  idem,  1913,  vi,  73. 


46 


MORPHOLOGY 


processes.  There  is  no  doubt  that  these  neutrophil  cells  repre- 
sent the  pars  intermedia  of  mammals,  for  they  are  found  invading 
the  nervous  outgrowths  which  are  composed  of  neuroglial  and 
ependymal  cells  and  fibres.  The  pars  nervosa  proper,  then,  is  a 
branching  structure,  and  is,  therefore,  deeply  indented  by  collec- 
tions of  the  chromophobe  cells.  In  the  centre  of  the  main  body 
of  the  pars  nervosa  lies  the  cavity  of  the  infundibulum,  which 
is  directly  connected  with  the  third  ventricle  of  the  brain. 


S 


' 


Fig.  26. 

<—  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  cod  (gadus  morrkua).  (After 
Herring.)  A,  distal  epithelium;  B,  juxtaneural  epithelium;  C,  cavity  of  infun- 
dibular process ;  D,  pars  nervosa ;  E,  saccus  vasculosus. 

Behind  the  pituitary  of  the  cod  and  in  the  mid-line  lies  the 
saccus  vasculosus,  the  interior  of  which  is  also  in  direct  com- 
munication with  the  ventricle. 

In  the  common  eel  (anguilla  vulgaris),  which  has  been  investi- 
gated by  Tilney1,  we  reach  an  interesting  stage  in  the  evolution 
of  the  pituitary  (fig.  27).  According  to  this  investigator,  the 
pars  anterior  is  well  defined  in  a  central  and  two  lateral  masses, 
while  the  pars  posterior  is  almost  equal  in  size  to  the  pars 
anterior.      There  is  no  cleft  between  the  two  parts.      The  cells 


1  Tilney.   F.,   Memoirs    Wistar    Instit.    Anat.    and    Biol,    Philadelphia,    1911 
(No.  2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     47 

in  the  central  mass  of  the  pars  anterior  are  arranged  in  definite 
acini,  and  in  staining  reaction  are  strongly  basophil ;  on  the 
other  hand,  those  in  the  lateral  portions  are  acidophil,  and  are 
arranged  in  columns  with  intervening  blood-spaces.  The  pars 
posterior  shows  a  hollow  infundibular  process  which  forms  abori- 
zations  backwards  and  downwards,  giving  rise  in  these  directions 
to  primary,  secondary  and  tertiary  diverticula  all  of  which  are 
hollow  and  are  lined  with  ependyma-cells.  The  spaces  between 
these  branches  are  filled  with  lightly  staining  basophil  epithelial 
cells  ;    in  other  words,  the  hollow  infundibular  projections  bury 


Fig.  27. 

<r-  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  eel  (anguilla  vulgaris).  {After 
Tilney.)  PA,  distal  epithelium;  PI,  juxtaneural  epithelium;  C,  infundibular 
cavity ;  PL,  lateral  masses. 

themselves  in  a  mass  of  pars  intermedia  (juxtaneural)  epithelium. 
This  arrangement  gives  the  pars  posterior  the  appearance  of  an 
actively  secreting  gland  the  cells  of  which  surround  lumina 
leading  to  the  ventricle  of  the  brain  ;  and  there  can  be  no  doubt 
that  it  is  partly  this  interesting  disposition — which  is  also  de- 
scribed by  Gentes — that  has  led  to  belief  that  the  pressor  sub- 
stance produced  in  the  pars  posterior  is  conveyed  to  the 
cerebrospinal  fluid  in  the  third  ventricle.  Herring1  has  sup- 
ported this  view,  which  he  originated,  by  other  evidence  that 
will  be  discussed  in  the  appropriate  place. 


1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 


48  MORPHOLOGY 


AMPHIBIA 

The  commoner  species  of  amphibian  animals  have  been  in- 
vestigated by  several  observers :  Haller1,  Sterzi2,  Gentes3  and 
Herring4,  especially,  have  contributed  valuable  information  con- 
cerning these  creatures. 

Ecaudata. — Gentes  investigated  two  genera  of  ecaudata 
(bnfo  vulgaris  and  rana  esculenta),  and  found  that  there  were  no 
essential  differences  between  them  in  regard  to  the  pituitary. 
Tilney  examined  rana  sylvatica.  The  descriptions  of  Gentes, 
Tilney  and  Herring  are  more  or  less  in  agreement,  in  regard  to 
the  main  particulars,  with  those  of  the  earlier  observers  ;  con- 
sequently the  pituitaries  of  this  order  of  amphibians  must  closely 
resemble  each  other. 

The  organ  is  triangular  in  shape  and  the  pars  nervosa  and 
juxtaneural  epithelium  are  situated  above  and  in  front  of  the 
distal  epithelium.  Tilney  could  find  no  residual  lumen  in  the 
adult  animal,  but  Gentes  represents  this  cavity  to  be  of  con- 
siderable size.  The  last-named  observer  points  out,  also,  that 
there  is  a  number  of  large  vessels  in  the  pars  nervosa,  a 
phenomenon  which  may  be  of  physiological  importance. 

There  is  a  considerable  difference  between  the  amphibian 
pituitary  and  that  seen  in  the  bony  fishes  and  reptiles.  In  the 
animals  under  discussion  the  posterior  lobe  is  relatively  small ; 
indeed,  in  some  cases  it  is  little  more  than  the  adjacent  wall 
of  the  hollow  infundibular  process — the  '  hypophyseal  recess  ' 
of  Gentes  being  entirely  absent. 

The  juxtaneural  epithelium  is  closely  attached  to  this  im- 
perfect infundibular  lobe  which  may  slightly  indent  the  epi- 
thelial layer,  but  there  is  no  hollow  branching  as  in  teleosts. 
The  cells  of  the  juxtaneural  epithelium  are  closely  packed  and 
are  chromophobe  in  their  staining  affinities. 

The  pars  anterior  is  entirely  eosinophil  in  its  tinctorial  affinity 
(Tilney),  and  according  to  Gentes  there  is  no  connective  tissue 

1  Haller,  B.,  Morphol  Jahr.,  1896,  xxv,  31. 

2  Sterzi,  A.  (quoted  by  Gentes3),  Atti  delV  Accad.  Sci.  Veneto-Trentino-Istriana, 
1904,  i,  72. 

3  Gentes,  L.,  Soc.  Sci.  d' Arcachon,  Travaux  de  labored.,  Bordeaux,  1907,  129. 

4  Herring,  P.  T.;  Quart.  Journ.  Exper.  Physiol.,  1913.  vi,  73, 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     49 

between  the  cells,  but  a  very  extensive  vascular  sinusoidal 
arrangement  of  the  vessels.  Attached  on  either  side  to  the 
central  part  of  the  pars  anterior  are  two  lateral  masses,  called 
by  Gaupp1  the  lateral  lobes  of  the  hypophysis. 


"*^^v. 


"'X, 


•  .'■■'  *  -■ 


Fig.  28. 

<—  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  frog  (rana  esculenta).  (After  Gentes.) 
I,  infundibular  process ;  H,  infundibular  angle;  PN,  pais  nervosa;  PI,  juxtaneural 
epithelium;  PA,  distal  epithelium;  LC,  connective  tissue  separating  two  lobes; 
BC,  base  of  cranium ;  VE,  lymphatic-  vesicle. 

Caudata. — In  the  salamander  (salamandra  maculosa)  the 
pituitary  has  a  very  similar  formation  to  that  seen  in  the 
frog  (fig.  29).  There  is,  however,  one  important  distinction, 
namely,  the  glandular  epithelial  elements  of  the  pars  anterior 
arc  arranged  round  blood-channels,  as  in  the  cases  of  some 
elasmobranchs   (see  fig.   25). 

In  amphibians,  then,  there  are  several  points  of  importance  : 
first,  the  small  extent  of  the  pars  nervosa,  which  is  merely 
formed  by  the  wall  of  the  hollow  infundibular  process  abutting 

1  Gaupp,  E.,  Nervensystem.  A.  Eckefs  und  R.  Wiedersheim's  Analomie  des 
Frosches,  1897,  94. 

4 


50 


MORPHOLOGY 


%S*L 


■  -.  ■ :  ■.  ■:>¥*^       • ■»,.   ^; 


Fig.  29. 

<-  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  salamander  {salamandra  maculosa). 
{After  Gentes.)  I,  infundibular  process;  PN,  pars  nervosa;  JN,  juxtaneural 
epithelium  ;  DE,  distal  epithelium  ;  C.  capillary  gland. 


Fig.  30. 

<—  Anterior  direction. 

Median  sagittal  section  of  the  pituitary  of  the  lizard  {laccrta  viridis).  {After 
Gentes.)  I,  infundibular  process ;  H,  infundibular  recess ;  PN,  pars  nervosa;  JN, 
juxtaneural  epithelium  ;  DN,  distal  epithelium;  C,  residual  cavity. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     51 

on  the  hypophysis ;  second,  the  well-defined  but  limited  pars 
intermedia  and  the  extensive  distal  epithelial  portion  in  which 
the  cells  are  closely  related  to  its  internal  blood -supply. 

REPTILIA 

In    some    of    the   reptiles — lacerta  viridis   (Gentes,    Herring)  ; 
alligator    mississijppiensis    (Tilney) — an    arrangement    similar    to 


'>. 


^w^^^0^ 


Fig.  31. 

Median  sagittal  section  of  the  pituitary  of  the  tortoise  (testiido  europoea). 
(After  Gentes.)  H,  infundibular  recess;  PN,  pars  nervosa;  JN,  juxtaneural 
epithelium ;  DE,  distal  epithelium ;  C,  residual  cavity. 

that  just  described  is  found  in  regard  to  the  pars  intermedia 
and  pars  nervosa,  but  the  ramifications  of  the  latter  are  greater 
(fig.  30).  In  some  reptiles  the  pars  '  posterior  '  is  superior  to 
the  pars  '  anterior ',  which  forms  as  it  were,  a  saucer  below  it 
(fig.    31).      We    shall   see   that  this  cup-and-saucer   arrangement 


52  MORPHOLOGY 

also  obtains  in  some  of  the  higher  mammals.  According  to 
Tilney  two  types  of  cells  are  found  in  the  pars  anterior  of  the 
alligator — acidophils,  which  are  centrally  placed,  and  basophils 
at  the  periphery.  The  residual  lumen  or  cleft  is  usually  quite 
distinct. 

In  the  tortoise  (testudo  europcea),  according  to  Gentes,  the 
pituitary  is  more  like  that  seen  in  birds  and  mammals  than  is 
the  case  in  most  other  reptiles.  There  is  very  little  irregularity 
in  the  surface  of  the  pars  nervosa,  and  there  is  an  anterior 
tongue  of  the  distal  epithelial  portion  (fig.  31). 

Herring1,  also,  has  described  the  histological  features  of  the 
reptilian  (testudo  grceca)  pituitary.  He  found  that  the  distal 
epithelial  portion  is  made  up  of  numerous  acini  lined  with 
cubical  or  columnar  epithelium  and  filled  with  secretion. 

AVES 

Gallus  domesticus. — In  regard  to  the  fowl,  which  has  a  type 
of  pituitary  common  to  many  birds,  investigators  have  not  been 
entirely  in  agreement.  Hannover2  and  Herring3  state  that  the 
anterior  lobe,  which  is  in  front  of  and  below  the  posterior  lobe 
(fig.  32),  is  made  up  of  undifferentiated  cells,  and,  in  consequence, 
resembles  parathyroid  tissue.  These  cells  are,  they  state,  small 
and  finely  granular  and  are  unlike  the  cells  in  the  mammalian 
pituitary.  On  the  other  hand,  Sterzi4,  Gentes5  and  Tilney6 
describe  chromophil  cells  in  the  pars  anterior.  The  last-named 
also  describes  basophils  which,  he  says,  are  situated  almost 
entirely  on  the  anterior  margin  of  the  cleft;  whereas,  according 
to  the  same  observer,  the  eosinophils  occupy  the  rest  of  the 
pars  anterior,  some  staining  lightly,  others  darkly. 

Herring  was  unable  to  find  a  cleft,  but  Tilney  describes  an 
"  appreciable  space  or  cavity  ". 

In  passing,  it  may  be  noted  that  Tilney  appears   to  consider 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol.,  1913,  vi,  73. 

2  Hannover,  A.,  Becherches  Microscopiques  sur  le  System  Nerveux,  1844,  26. 

3  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  261. 

4  Sterzi,  A.  (quoted  by  Gentes),  Atti  delV  Accad.  Sci.  Veneto-Trentino-Istriana., 
1904,  i,  72. 

5  Gentes,  L.,  Soc.  Sci.  cF Arcachon,  Travaux  des  laborat.,  Bordeaux,  1907,  129. 

3  Tilney,  F.,  Memoirs  Wistar  Instil  Anal  and  Biol,  Philadelphia,  1911 
(No.  2),   1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     53 

cells   that   would   ordinarily  be  described  as    '  chromophobe  '  as 
'  basophil '. 

I  have  myself  examined  the  fowl's  pituitary  and  have  come 
to  the  conclusion  that  the  divergence  of  opinion  in  regard  to 
the  character  of  the  cells  in  the  distal  epithelial  portion  is  due 
to  the  fact  that  different  observers  have  examined  pituitaries 
in  different  physiological  states ;  that  is  to  say.  that  if  hens  be 
examined  the  appearance  of  the  pituitary  will  be  found  to  vary 


Fig.  32. 
Anterior  direction. 


Median  sagittal  section  of   the  pituitary  of   the  fowl  (gallus  domesticus).      (After 
Herring.)     A,  distal  epithelium  ;  B,  juxtaneural  epithelium  ;  C,  third  ventricle. 


with  the  state  of  genital  activity — a  subject  I  shall  discuss  more 
fully  in  the  appropriate  place  (p.  87). 

In  the  cock  and  in  the  egg-laying  hen  I  have  found  that  the 
distal  epithelial  portions  are  very  similar :  there  are  many 
eosinophil  cells,  with  small,  round,  dark  nuclei,  mixed  indis- 
criminately with  neutrophil  cells  having  large  nuclei  which  show 
a  chromatin  network— an  average  field  (fig.  G6a,  p.  90)  shows 
a  kaleidoscopical  disregard  of  order  and  arrangement.  It  is  in 
the  brooding  state  that  the  cells  assume  a  uniform  type,  as  we 
shall  see  later. 


54  MORPHOLOGY 

I  have  been  unable  to  detect  any  cleft,  but  it  is  common  to 
see  in  sections  artificial  separation  of  the  distal  epithelial  cells 
from  the  neural  process. 

The  pars  nervosa  in  the  fowl  is  convoluted  and  hollow,  and 
opens  into  the  third  ventricle.  The  pars  intermedia  is  very- 
poorly  developed,  and  is  not  spread  uniformly  on  the  pars 
nervosa  ;    the  neck,  however,  is  thickly  covered. 

In  this  short  survey  of  the  morphology  of  the  pituitary  of 
creatures  below  the  mammals  several  important  facts  have  been 
recorded.  First,  in  the  elasmobranchs  the  pars  posterior  is  not 
always  present.  Second,  the  cells  of  the  pars  anterior  do  not 
show  acidophil  and  basophil  differentiation  in  the  lowest  verte- 
brate forms  investigated  ;  and  in  some  the  cells  are  arranged 
in  acini  with  capillaries  in  the  lumina.  Third,  the  pars 
nervosa  when  present  usually  shows  a  hollow,  branched  or 
convoluted  arrangement ;  and,  if  we  were  to  judge  only  by 
appearance,  the  close  application  of  the  pars  intermedia  cells  to 
these  hollow,  branching  processes,  would  lead  us  to  the  conclu- 
sion that  the  partes  intermedia  and  nervosa  together  form  a 
gland  that  discharges  its  secretion  into  the  third  ventricle. 

All  these  points  will  lie  before  us  later  when  an  attempt  is 
made  to  discuss  the  functions  of  the  pituitary. 

From  this  point  we  may  continue  our  study  of  the  compara- 
tive anatomy  by  a  consideration  of  the  pituitaries  of  represent- 
atives of  different  orders  of  mammals,  some  of  which  have 
repeatedly  been  described  not  only  by  the  writers  already  named, 
but  also  by  Lothringer1,  Trautmann2  and  many  others. 

It  may  be  mentioned  in  the  first  place  that  there  appears  to 
be  some  relationship  not  only  between  the  general  contour  of 
the  pituitary,  and  the  relative  positions  of  the  pars  nervosa  to 
the  epithelial  portions,  but  also  between  the  general  shape  of 
the  skull  and  the  depth  of  the  pituitary  fossa.  Thus  we  find 
that  in  long  flat-headed  animals,  such  as  the  dog  (fig.  51)  and 
the  hedgehog  (fig.  54),  the  pars  nervosa  is  superior  or  supero- 
posterior  to  the  epithelial  portions,  and  the  fossa  is  shallow; 
whereas  in  the  short-headed  animals,  such  as  the  ornithorhynchus 
(fig.  33),  the  cat  (fig.  47),  the  lemur  (fig.  56),  the  monkey  (fig.  59) 

1  Lothringer,  S.,  Arch.  f.  Mikr.  AnaL,  1886,  xxviii,  257. 

2  Trautmann.  A.,  Arch.  f.  Mikr.  Anat.,  1909,  lxxiv,  311. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     55 

and  Man  (fig.  60),  the  pituitary  is  situated  in  a  deep  fossa,  and 
the  pars  nervosa  is  more  directly  posterior  to  the  epithelial 
portions. 


MAMMALIA 

Monotremata. — Of  the  most  primitive  mammalian  order 
(monotremata)  only  two  species  now  exist — the  echidna  and  the 
ornithorhynchus.  I  have  had  the  opportunity  of  examining 
these  animals ;  but  my  material  in  regard  to  the  echidna  was 
not  sufficiently  well  preserved  to  enable  me  to  make  satisfactory 
histological  examinations. 

The  pituitary  of  ornithorhynchus  anatinus  which  has  not,  so  far 
as  I  know,  been  described  previously,  is  singularly  interesting,  in 
that   it   shows   certain  character- 
istics   of    the    higher    fishes    and  "v\ 
some  reptiles  with  respect  to  the 
pars    posterior.       The     organ    is 

situated   in    a    fairly  deep  fossa  ;  :  ^. 

consequently  its   outline  is  found  ■■■  ■''■':^ 

to    be    roundly    oval    in    shape.  / 

The  pars   anterior   is   round   and 

convex  in  front  and  slightly  con-  i^l:ii^.-      * 

cave  behind.     This  posterior  sur-  FIG.  33. 

face  is  separated  by  a  cleft  from 

Anterior  direction.  — > 
the     pars     posterior     which     fits 

closclv  to   it   (fio;     33)  Median    sagittal    section    of    the 

„,.',,,  .  pituitary  of  ornithorhynchus. 

The  cells  of  the  pars  anterior  x  15. 

are  both  chromophil  and  chromo- 
phobe. The  former  are  for  the  most  part  finely  granular 
and  eosinophil  ;  but  here  and  there  coarsely  granular,  spherical 
cells  are  to  be  seen,  and  these  show  gradations  from  a  bluish- 
pink  acidophilia  to  purple  basophilia — variations  that  probably 
represent  transitional  phases  from  acidophilia  to  basophilia. 
The  nuclei  of  the  large  dark  cells  are  eccentric  in  position 
(fig.  34).  The  chromophobe  cells  are  shrunken  and  ragged  and 
have  clear,  lightly  staining  nuclei.  Towards  the  infundibular 
stalk  the  cells,  here  and  there,  have  an  acinous  arrangement. 
Granular  secretion  and  colloid  material,  however,  are  very 
scarce. 


56 


MORPHOLOGY 


There  is  a  considerable  amount  of  supporting  tissue  among 
the  cells  of  the  pars  anterior,  especially  towards  the  periphery, 
where  spindle-shaped,  kite-shaped,  and  long  triangular  nuclei 
stand  out  prominently  among  the  epithelial  cells.  Blood-spaces 
are  to  be  seen,  but  they  are  not  very  conspicuous. 

The  cells  of  the  pars  intermedia  of  the  ornithorhynchus 
entirely  surround  the  pars  nervosa  in  a  thick  layer  ;  and  from 
the  cellular  capsule  columns  of  cells  pass  deeply  down  and  even 
completely  through  the   pars  nervosa  (figs.  35  and  36).      These 


t.d  *'  ■  *    •  \ 


Fig.  34. 
Section  of  the  pars  anterior  of  the  orniihorhynchns. 


X  250. 


cells  are  polygonal  in  outline,  are  neutrophil  in  staining  reaction 
and  have  rounded  nuclei ;  they  appear  to  have  no  supporting 
tissue.  A  few  small  masses  of  granular  secretion  are  to  be 
found  among  the  cells,  but  there  is  no  evidence  of  any  vesicular 
formation. 

The  pars  nervosa  is  peculiar  in  that  not  only  is  it  channelled 
by  the  cells  of  the  pars  intermedia,  but  also  it  is  divided  up  into 
lobules  by  fine,  though  dense,  connective  tissue  trabecular  in 
which  flattened  nuclei  may  be  seen.  It  is  noteworthy,  also,  that 
the  invading  columns  of  cells  of  the  pars  intermedia  pass  down 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     57 


Fig.  35. 
Section  of  the  partes  intermedia  and  nervosa  of  omitJwrhynchus, 


X60. 


2> 


o 


9     9  ©        o 


9;  T/i 


9© 


0 
& 


4$  & 

Fig.  36. 

Section  of  the  pars  nervosa  of  omithorhynchus,  showing  a  column  of 
pars  intermedia  cells  passing  down. 

X  400 


58  MORPHOLOGY 

channels  denned  on  either  side  by  a  layer  of  thin,  tough  con- 
nective tissue  (fig.  36).  There  is  distinct  evidence,  too,  that 
those  trabecular  which  do  not  enclose  ingrowing  columns  of 
intermedia  cells  are  nevertheless  channels  ;  that  is  to  say,  the 
connective  tissue  is  composed  of  two  separate  layers.  There  is, 
occasionally,  some  secretion  to  be  found  among  the  epithelial 
cells  enclosed  in  the  trabecular,  and  not  infrequently  these  cells 
migrate  and  invade  the  neuroglial  tissues  proper,  and  even  give 
rise  to  the  formation  of  the  so-called  '  secretion-bodies '. 

As  already  stated,  this  invasion  of  the  pars  posterior  by 
columns  of  juxtaneural  epithelium  recalls  the  branching  arrange- 
ment of  the  pars  nervosa  seen  in  many  fishes  and  reptiles  ;  and 
it  represents,  no  doubt,  a  structural  arrangement  whereby  an 
intimate  and  extensive  relationship  is  established  between  the 
pars  intermedia  and  pars  nervosa. 

Marsupialia.— The  pituitary  of  the  marsupial  has  been  de- 
scribed by  Tilney1  in  the  case  of  the  opossum  (didelphys 
virginiana).     I,  also,  have  examined  the  pituitary  of  this  animal. 


Median  sagittal  section  of  the  pituitary  of  the  opossum  {didelphys  virginiana). 

X  15. 

The  pars  nervosa  is  situated  superiorly,  or  slightly  supero- 
posteriorly,  to  the  distal  epithelial  portion  (fig.  37).  Tilney 
describes  a  central  cavity  in  the  pars  nervosa  and  a  lumen 
through  the  stalk  leading  to  the  third  ventricle.  In  the  specimen 
examined  by  me — an  old  male — there  is  a  slit-like  central  cavity. 
1  Tilney,  F.,  Memoirs  Wistar  Instit.  Anat.  &  Biol.  Philadelphia,  1911  (No.  2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     59 

The  pars  nervosa  is  composed  of  neuroglial  elements  arranged 
in  a  peculiar  manner  ;  that  is  to  say,  there  is  a  dense  band 
folded  on  itself  like  the  lutein-layer  in  the  ovary.  Between 
the  folds  the  neuroglial  elements  are  loose.  It  is  possible  that 
the  convoluted  band  is  the  remains  of  the  edge  of  a  large  cavity 
lined  with  ependymal  cells,  which  existed  in  an  early  stage  of 
development. 

The  juxtaneural  epithelium  entirely  surrounds  the  pars  ner- 
vosa, and  is  for  the  most  part  composed  of  one  layer  only  of 


Fig.  38. 

Section  of  the  pituitary  of  the  opossum  (didelphys  virginiana).  showing  the  distal 
epithelium,  below  and  to  the  right,  separated  by  the  cleft  from  the  pars  nervosa 
which  is  covered  with  a  single  layer  of  juxtaneural  epithelium.     (Photomicrograph.) 

X  250. 

columnar  epithelium,  the  cells  of  which  have  large,  oval, 
central  nuclei.  Here  and  there  the  epithelial  investment  may 
be  two  or  three  cells  in  depth,  but  this  is  quite  exceptional. 
Tilney,  however,  describes  a  layer  several  cells  thick.  But  in 
the  specimen  examined  by  me  the  uniformity  of  the  single- 
cell  layer  was  remarkable  and  interesting  (fig.  38).  The  cells 
of  the  juxtaneural  epithelium  are  neutrophil. 

The  distal  epithelial  portion  is  separated   from   the    rest   of 
the  organ  by  a  wide  cleft ;   and  those  cells  which  abut  on  this 


60  MORPHOLOGY 

residual  lumen  are  flattened  on  the  surface  and  are  tightly 
packed  together  (fig.  38). 

The  distal  epithelium  is  abruptly  divided  into  two  parts  by 
differences  in  the  staining  affinities  of  the  cells.  In  the  anterior 
portion  the  cells  are  uniformly  lightly  basophil  or  chromophobe. 
The  smaller  cells  have  darkly  staining  nuclei,  and  the  larger 
cells  clear,  round,  central  nuclei.  In  the  posterior  portion 
brightly  staining  eosinophil  cells  with  small  dark  nuclei  are 
mixed  indiscriminately  with  large  chromophobe  cells  containing 
large,  round,  clear  nuclei. 

The  cells  of  both  parts  of  the  distal  epithelial  portion  are 
arranged  in  irregular  branching  columns.  There  are  numerous 
blood-spaces,  but  there  is  very  little  intercellular  connective 
tissue. 

Tilney  has  described  dark  basophils  and  colloid  secretion  in 
this  part  of  the  pituitary  of  the  opossum.  I  have  been  unable 
to  find  either  darkly  staining  basophil  cells  or  colloid  material. 

Ungulata.— The  commoner  domestic  species — the  ox,  the 
pig  and  sheep — have  probably  been  examined  by  numerous 
observers,  but  there  are  very  few  accounts  of  the  pituitaries  of 
the  sheep  and  pig. 

The  pituitary  of  the  ox  (bos  taurus)  has  been  described  by 
Lewis,  Miller  and  Matthews1,  by  Herring2  and  others. 

The  whole  gland  is  oval  and  is  placed  in  a  deep  fossa  with 
a  narrow  outlet  for  the  infundibular  stalk.  The  anterior  lobe 
is  oval  and  is  separated  from  the  posterior  lobe  by  a  cleft.  The 
pars  posterior  is  crescentic  in  shape — the  concave  aspect  abut- 
ting on  the  cleft  (fig.  39).  The  front,  the  lateral  and  the  lower 
aspects  of  the  pars  nervosa  and  the  entire  circumference  of  the 
neck,  are  covered  with  cells  of  the  pars  intermedia,  which  con- 
sists of  a  layer  many  cells  deep.  This  layer  is  thickest  at  the 
bottom  and  in  the  middle  of  the  cleft  (fig.  39).  The  pars 
nervosa  is  solid,  and  there  is  no  invasion  or  dipping  down  of 
the  pars  intermedia,   which  forms  an  unbroken  line. 

The  anterior  lobe  is  made  up  of  brightly  staining  eosinophil 
cells,  mixed  indiscriminately  with  chromophobe,  or  faintly  baso- 
phil, cells.     No  dark  basophils  are  to  be  observed.     The  general 

1  Lewis,  D.  D.,  J.  L.  Miller  and  S.  A.  Matthews,  Amer.  Arch.  Med.,  1911,  vii,  785. 

2  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol.,  1914,  viii,  245. 


COMPARATIVE    ANATOMY   OF   THE   PITUITARY     61 

arrangement  of  the  cells  is  more   or  less  acinous  ;    but  little  or 
no  colloid  material  is  to  be  found. 

The  pars  intermedia  consists  of  the  usual  faintly  basophil 
cells  which  may  assume  an  acinous  arrangement  near  the  neck. 
A  striking  feature  of  the  pars  intermedia  in  this  animal  is 
the  number  of  large  blood-vessels  lying  among  the  epithelial 
cells.  The  pars  nervosa  presents  the  same  characteristic  in 
regard  to  the  blood-vessels,  which  are  extremely  numerous  and 
large  (fig.  40).  In  no  other  pituitary  that  I  have  examined  has 
there  been  such  a  profusion  of  vessels  through  the  whole  of 
the  nervous  process. 


Fig.  39. 

Median  sagittal  section  of  the  pituitary  of  the  ox  (bos  taurus). 

X  7  'O. 

I  have  been  unable  to  find  secretion-bodies  in  the  pars 
nervosa.  Herring  states  that  "  they  are  very  pronounced "  ; 
but  Lewis,  Miller  and  Matthews  assert  that  they  are  not  a 
common  phenomenon. 

The  pituitary  of  the  sheep  (ovis  aries)  has  been  described  by 
Peremcschko1  and  Tilney2.     I,  also,  have  examined  this  organ. 

It  is  stated  by  Tilney  that  the  "  hypophysis  "  —  presum- 
ably the  pars  anterior — of  this  animal  is  divided  and  sub- 
divided by  "  a  rich  trabecular  system  "  which  gives  it  "  the 
semblance  of  a  tabulated  organ"2.     Tilney  also  states  that  the 

1  Pererneschko  (no  initial  in  original),  Virchoics  Arch.,  1867,  xxxviii,  329. 

2  Tilney,  F.,  Memoirs  Wistar  Instil.  Anal,  and  Biol.,  Philadelphia,  1911 
(No.  2),  1. 


62 


MORPHOLOGY 


Fig.  40. 


Section  of  the  pars  nervosa  of  the  ox  (bos  tavrus).  showing  many 
blood-vessels  containing  blood. 


X  100. 


Si 


Fig.  41. 


Median  sagittal  section  of  the  pituitary  of  the  sheep  (ovis  aries). 
neural  process  is  seen  to  the  left  of  the  picture. 


The  small 


X  7-5. 


COMPARATIVE   ANATOMY   OF   THE    PITUITARY     63 

pars  anterior  is  composed  chiefly  of  eosinophil  cells,  each  of 
which  appears  to  have  its  definite  place  in  the  wall  of  a  vesicle. 

There  is  no  doubt  that  the  pars  anterior,  especially  at  the 
inferior  periphery,  is  subdivided  into  lobules  by  wide  spaces 
(fig.  41).  I  think  there  is  no  doubt  that  these  are  blood- 
channels,  for  they  are  lined  with  endothelium  (fig.  42). 

There  is  a  rich  vascular  system,  and  the  epithelial  cells  are 
arranged  in  a  radial  fashion  around  the  sinuses  (fig.  43). 

The  eosinophils  are  certainly  most  prominent,  but  there  are 


V*. 

Fig.  42. 

Section  of  the  distal  epithelial  portion  of  the  sheep  (ovis  aries)i  showing 
spaces  lined  with  endothelium. 

X  150. 

many  faintly  basophil,  or  neutrophil,  cells  which  arc  often  found 
in  large  masses. 

The  pars  intermedia,  which  shows  the  usually  faintly  basophil 
staining  affinity,  is  many  layers  in  depth,  and  invests  the  pars 
nervosa  in  front  and  at  the  sides,  and  surrounds  the  stalk. 
The  cells  are  arranged  in  columns  radiating  from  the  surface  of 
the  pars  nervosa,  and  there  is  much  supporting  tissue.  Colloid 
s( crction  may  be  found  in  the  cleft. 

The  pars  nervosa,  which    is  solid,  is  very  small,  and  I  have 


64 


MORPHOLOGY 


been   unable   to   find  blood-vessels,    except   in   close  relation   to 
the  pars  intermedia. 


- 


- 


0'  -v^t 


-  -    '  *\ 


. 


' 


-• 


i 


■ 


- 


■. 


Fig.  43. 


9 


Section  of  the  distal  epithelial  portion  of  the  sheep  (ovis  aries),  showing  radial 
arrangement  of  the  cells  around  a  blood-channel. 

X375. 

I  have,  also,  examined  the  pituitary  of  the  pig  (sus  domesiicus). 
In  this  animal  the  organ  is  a  long  oval  in  shape  (fig.  44).     The 

anterior  lobe  is  bluntly  rounded 
anteriorly,  and  is  slightly  concave 
behind  to  accommodate  the  pars 
posterior  which  is  pear-shaped,  and 
is  separated  from  the  pars  anterior 
by  a  cleft. 

The  pars  nervosa  is  entirely 
surrounded  by  the  pars  intermedia, 
which  however  does  not  form  a 
thick  layer  except  in  the  neighbour- 
hood of  the  cleft  and  around  the 
stalk,  which  is  entirely  covered. 

The  pars  anterior  has  histological  features  exactly  similar  to 
those  already  described  in  regard  to  the  pituitary  of  the  ox. 

The  pars  intermedia  shows  the  usual  staining  reaction.     Here 


Fig.  44. 

Median  sagittal  section  of  the 
pituitary  of  the  pig  {sus  domesiic- 
us). 

X7-5. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     65 

and  there  wedge-shaped  masses  of  cells  dip   down  a  short  way 
into  the  underlying  pars  nervosa. 

The  pars  nervosa  shows  a  peculiar  whorled  arrangement  of 
the  fibres,  the  -general  trend  of  which  is  towards  the  stalk.  A 
number  of  blood-vessels  is  to  be  observed  in  this  structure,  but 
not  so  many  as  in  the  case  of  the  ox.  A  few  granular  bodies 
may  be  seen  in  the  neighbourhood  of  the  pars  intermedia. 

Rodentia. — Tilney1  states  that  in  rodents  generally,  the  pars 
nervosa  lies  above  the  rest  of  the  pituitary.  Such,  however,  is 
certainly  not  the  case  in  the  guinea-pig  and  the  rabbit. 

This  author  also  states  that  in  the  rat  (mus  decumanus)  the 

cells  of  the  distal  epithelial  portion 
|v;\  are  basophil  in  the  neighbourhood 

k    of  the  narrow  cleft,  and  eosinophil 
:'    in  the  rest  of  the  distal  epithelial 
portion,  and  that  the  juxtaneural 
epithelium  forms  a  deep  layer  of 
•  45,  faintly  basophil  cells.      In  my  ex- 

Median  sagittal  section  of  the  pituitary  perience,  however,  deeply  staining 
of  the  guinea-pig  (cavia  familiaris).      ,  ,  .,  ,  . , 

1  J  x  j5    basophils  are  not  seen  in  the  pars 

anterior  of  the  rabbit  (Upus  cunic- 

ulus),  the  guinea-pig  (cavia  familiaris)  or  the  dormouse  (mus- 
cardinus  avellanarius),  nor  is  granular  secretion  or  colloid  material 
to  be  observed.  Faintly  ba- 
sophil— really  chromophobe 
— cells  are  fairly  numerous, 
but  most  of  the  epithelial 
cells  of  the  pars  anterior  are 
lightly  eosinophil. 

In  the  guinea-pig  the 
whole  pituitary  is  somewhat 
elongated,  and  there  is-  a 
well-defined    cleft    (fig.    45). 

In    the    rabbit   the    cleft    is  ^G-  46- 

extremely   narrow,    so   much    Median  sagittal  section  of  the  pituitary  of 
so    that     the    very    regular  the  rabbit  (lepus  cunicuhs). 

X  !£)• 

and    thick    pars    intermedia 

appears  to  lie  almost  directly  on  the  pars  anterior  (fig.  46). 

1  Tilney,  F.,  Memoirs  Wistar  Inslit.  Anat.  and  Biol.,  Philadelphia,  1911  (No.  2),  1 

5 


66  MORPHOLOGY 

The  pars  intermedia  (juxtaneural  epithelium)  thickly  covers 
the  pars  nervosa.  These  cells  stain  faintly  with  basic  dyes— 
a  staining  reaction  that  is  universal  in  regard  to  the  cells  of 
the  pars  intermedia  of  all  mammals. 

Carnivora. — Of  this  mammalian  order  the  two  most  com- 
monly investigated  types  are  the  domestic  dog  {canis  familiaris) 
and  cat  (felis  domestical).  These  animals,  however,  present  in 
their  pituitaries  widely  different  characteristics. 


' "-"  '  '-"      •',"'' 


Fig.  47. 

Median  sagittal  section  of  the  pituitary  of  the  cat  (felis  domestica).     The  part 
enclosed  in  the  white  lines  is  shown  more  highly  magnified  in  figure  48. 

X  15. 

In  the  cat  the  pituitary  is  situated  in  a  very  deep  fossa  ; 
consequently  the  pars  nervosa  is  placed  posteriorly,  and  the 
whole  organ  is  almost  round  in  shape  (fig.  47).  Probably  the 
best  description  of  this  pituitary  has  been  given  by  Herring1, 
who  has  directed  special  attention  to  the  hollow  space  to  be 
found  in  the  pars  nervosa  and  the  opening  through  the  neck 
which  connects  the  cavity  with  the  third  ventricle.  This  space 
and  the  channel  are  lined  with  ependymal  cells.  Curiously,  no 
1  Herring,  P.  T.,  Qtoart.  Journ.  Exper.  Physiol,  1908,  i,  121. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     67 

mention  is  made  of  this  cavity  by  Tilney  in  his  description  of 
the  cat's  pituitary,  and  his  account  is  singularly  poor  in  other 
respects,  for,  contrary  to  his  statement,  there  is  usually  a 
considerable  amount  of  secretion  in  the  particularly  well- 
developed  acini  in  the  neighbourhood  of  the  neck  (fig.  48). 
This  acinous  formation  often  extends  along  the  base  of  the 
brain,  under  the  third  ventricle,  in  a  most  definite  manner  ; 
and  the  acini,   in  this  region,   are    widely  separated   from    one 


Fig.  48. 

Section  of  the  pituitary  of  the  cat  (felis  clomestica),  showing  more  highly 
magnified  the  part  enclosed  in  white  lines  in  figure  47. 

X  50. 

another  by  an  exceeding  vascular  connective  tissue  stroma 
(ng.  49). 

The  juxtaneural  epithelial  cells  (pars  intermedia)  in  the  cat 
completely  surround  the  pars  nervosa  and  the  neck,  and  in 
some  places  the  cells  form  wedge-shaped  masses  projecting  in- 
wards (fig.  47).  These  juxtaneural  cells  stain  rather  more 
deeply  than  usual  with  the  basic  dyes.  Supporting  spindle- 
shaped  cells  are  always  found  in  this  situation  (fig.  50). 

The   pars   anterior   is   extremely  vascular,  and  the  epithelial 


68 


MORPHOLOGY 


^,-y 


^ctftfi*     ft 

-  vV*  ->  •   in 

Fig.  49. 
Section  of  the  reticulated  portion  of    the  pars   intermedia  of   the  cat  (felis 
domestica),  showing  the  vesicular  arrangement  of  the  cells  which  are  lying  in  a 
loose  connective  tissue  stroma  containing  large  blood-vessels. 

X250. 


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Fig.  50. 

Section  of  the  pars  intermedia  of  the  cat  (felis  domestica)  where  it  abuts 

on  the  cleft,  showing  supporting  spindle-shaped  cells. 

X  700. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     69 

cells  form  cither  an  arrangement  of  short  branching  columns, 
resembling  the  disposition  of  heart-muscle,  or  a  more  distinctly 
acinous  grouping.  The  cells  are  for  the  most  part  eosino- 
phil, but  many  show  a  hazy,  moderately  deep  basophilia,  and 
it  is  not  uncommon  to  see  groups  of  quite  definite  basophils, 
although  their  colour-affinity  is  not  so  pronounced  as  in  the 
human  subject.  Here  and  there,  granular  secretion  may  be 
found  among  the  acini.  Pale  chromophobe  cells  with  large, 
clear  nuclei  are  plentiful.  As  in  practically  all  mammals  in 
which  the  pars  intermedia  is  well  developed,  the  cells  of  the 
distal  epithelial  part  bordering  on  the  cleft  are  closely  packed 
and  resemble  the  cells  of  the  juxtaneural  epithelium  in  appear- 
ance and  staining  reaction. 

. 

"/ ■'  '■  ■'■■    t**?.*v      'r^^Hi'*"-, 


Fia.  51. 

Approximately  median  sagittal  section  of  the  pituitary  of  the  dog  (canis  familiar  is). 
The  part  enclosed  in  a  white  ring  is  shown  more  highly  magnified  in  figure  52. 

X  15. 

In  the  pars  nervosa  of  this  animal  the  so-called  'secretion- 
bodies  '  are  frequently  seen.  The  importance  of  these  bodies 
will  be  discussed  later  (p.  97  and  following). 

In  the  dog  the  pituitary  is  situated  in  a  very  shallow  fossa 
at  the  base  of  the  skull ;  consequently  the  pars  nervosa  lies 
superiorly  to  the  epithelial  portions.  The  pars  nervosa  is  solid, 
but  there  is  a  slight  ventricular  depression  in  the  neck.  There 
is  a  wide,  irregular  residual  lumen  or  cleft,  and  the  pars  inter- 
media covers  unevenly  the  whole  of  the  neural  process,  while 
the  distal  epithelial  part  extends  below  the  cleft  like  a  saucer, 
with  the  largest  mass  of  cells  anteriorly  (fig.  51). 


70 


MORPHOLOGY 


The  '  anterior '  lobe  is  very  vascular  and  there  is  but  little 
supporting  tissue.  The  cells  are  arranged  in  cords,  and  are,  for 
the  most  part,  faintly  staining  both  with  acid  and  basic  dyes, 
more  especially  with  the  acid. 

Where  the  cells  of  the  pars  'anterior'  merge  with  those  of 
the  pars  intermedia  they  assume  a  more  acinous  arrangement, 
become  faintly  basophil  and  secrete  a  granular  substance.  I 
have  not  found  the  deeply  staining  basophils,  in  specific  areas 
in  the  distal  epithelial  portion,  as  described  by  Tilney1. 


tf > 


Fig.  52. 

Section  of  the  pars  intermedia  of  the  dog  (canis  familiaris),  showing  more 
highly  magnified  the  part  enclosed  in  a  white  ring  in  figure  51. 

X200. 

The  cells  of  the  juxta neural  portion  are  very  interesting  in 
this  animal.  As  is  shown  in  figure  51,  they  invest  completely 
the  pars  nervosa  and  form  wedges  dipping  into  it,  as  in  the 
cat.  A  peculiar  feature,  also,  in  this  animal  is  the  extensive 
acinous  arrangement  of  the  pars  intermedia  which  is  found  in 
every  part  of  it,  and  on  either  side  of  the  cleft  at  the  neck 
(fig.  52).  In  no  other  animal  that  I  have  examined,  not  ex- 
cepting  the   cat,  is    so    much   secretion   found,   not  only  in  the 

1  Tilney,  R,  Memoirs  Wistar  Instil  Anat.  and  Biol,  Philadelphia,  1911  (No.  2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     71 

epithelium  applied  to  the  pars  nervosa,  but  also  in  that  which 
is  distant  from  the  cleft — in  what  may  be  described  as  the  re- 
ticulated portion  of  the  pars  intermedia.  In  this  last  mentioned 
area  the  granular,  faintly  basophil  secretion  is  found  not  only  in 
the  acini  but  also  quite  indiscriminately  in  diffuse  masses  among 
the  cells  (fig.  53).  No  mention  is  made  of  this  secretory  activity 
of  the  pars  intermedia  of  dogs  by  Tilney. 


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Fig.  53. 

Section  of  the  pars  intermedia  of  the  dog  (canis  familiaris),  showing 
secretion  diffused  among  the  cells. 

X500. 

Insectivora. — I  have  examined  pituitaries  from  the  hedgehog 
(erinaceus  europceus)  —  hibernating  and  non-hibernating — but 
have  found  no  other  description  in  the  literature. 

The  organ  is  very  flat  and  lies  in  a  very  shallow  depres- 
sion in  the  base  of  the  skull  ;  consequently  the  pars  nervosa  lies 
superiorly  to  the  epithelial  portions  (fig.  54).  There  is  a  definite 
cleft  (residual  lumen)  which  is  placed  below  the  pars  'posterior', 
or  pars  superior  as  it  really  is.  The  pars  nervosa  is  solid,  and 
is  covered  with  a  nearly  even  layer  of  pars  intermedia,  lying 
from  four  to  eight  cells  deep. 


72 


MORPHOLOGY 


In  the  non-hibernating  animal — the  phenomenon  of  hiberna- 
tion will  be  discussed  presently  (p.  85) — we  find  that  in  the 
distal    epithelial  portion    the   cells  are   arranged    in    an    acinous 


Fig.  54. 

Anterior  direction  — >. 

Median  sagittal  section  of  the  pituitary  of  the  hedgehog  (erinaceus  europcetis). 

X  15. 

manner.  The  cells  are  of  three  types  :  first,  finely  granular, 
lightly  eosinophil  cells  with  large,  round,  faint  nuclei  are  found  to 
be  the  most  numerous  ;     second,  many  deeply  eosinophil  coarsely 


Fig.  55. 

Section  of  the  distal  epithelial  portion  of  the  hedgehog    (erinaceus   europceus), 
showing  irregularly  shaped,  darkly  staining  nuclei.     (Photomicrograph.) 

X  500. 

granular  cells  with  peculiar  very  darkly  staining — almost  ma- 
hogany- coloured— nuclei  of  irregular  shape  (fig.  55) ;  third,  a 
few    chromophobe,    or    faintly   basophil,    cells    with    large    clear 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     73 

nuclei — a  familiar  characteristic  of  this  type  of  cell — may  be 
seen.  Blood-vessels  and  blood-spaces  are  very  numerous,  and 
there  is  a  considerable  amount  of  supporting  connective  tissue. 

The  cells  of  the  pars  intermedia  (juxtaneural)  resemble 
very  closely  the  cells  of  the  distal  epithelial  portion,  being  for 
the  most  part  faintly  basophil  and  having  large  clear  nuclei ; 
yet  here  and  there  eosinophil  cells  with  dark  nuclei  are  to  be 
found — a  most  unusual  phenomenon.  There  are  numerous  large 
blood-vessels  immediately  below  the  cells  of  the  pars  intermedia 
among  which  are  to  be  seen  a  few  supporting  spindle-shaped  cells. 

It  will  be  noticed  that  in  figure  54  the  cleft  extends  down- 
wards posteriorly  into  the  cells  of  the  distal  epithelium.  The 
cells  on  the  posterior  aspect  of  this  extension  resemble  those  of 
the  juxtaneural  epithelium. 

Primates :  Lemuridce. — Next  in  an  ascending  scale  we  may 
consider  the  lemurs,  which,  possibly,  represent  the  common 
ancestors  of  the  higher  apes  and  man. 

Of  this  family,  I  have  examined  the  ring-tailed  lemur  (lemur 
catta),  which  is  nocturnal  in  its  habits.  I  have  been  unable  to 
find  any  account  of  the  hormonopoietic  organs  of  this  animal 
in  the  literature. 

Before  describing  the  pituitary,  I  may  mention  that  in 
the  animal  examined  (only  one  living  specimen  was  obtained) 
the  thyroid  resembled  in  its  histological  features  that  seen  in 
exophthalmic  goitre  in  human  subject.  This  interesting  fact 
becomes  more  striking  when  it  is  remembered  that  the  animal 
has  a  natural  condition  of  exophthal-  --r 

mos,  possibly  to  enable  it  to  see  well 
when  roaming  about  at  night. 

The    structure    of    the    pituitary,      £ 
too,  shows  peculiarities  for  which  it 
is  difficult  to  account. 

In  the  lemur  this  organ  is  situated  Fig.  56. 

in  a  deep  fossa  ;  consequently  it  is  Median  sagittal  section  of  the 
oval  in  shape,  and  the  pars   nervosa  pituitary  of  the  lemur  {lemur 

is  situated  posteriorly  (fig.  56).     The 

cells  of  the  pars  intermedia  cover  the  pais  nervosa  in  front, 
beneath  and  at  the  sides,  and  in  front  of  the  stalk.  Where  these 
cells    are    applied    to    the    body   of    the    pars  nervosa,   which    is 


74  MORPHOLOGY 

solid,  they  show  a  tendency  to  dip  down,  and  appear  to  form  islets 
of  cells,  as  shown  in  cross-section,  among  the  neuroglial  elements 
(fig.  57).  The  pars  intermedia  cells  stain  rather  more  deeply 
with  basic  dyes  than  is  usual  in  mammals — except,  perhaps, 
in  the  cases  of  the  dog  and  cat.  Numerous  supporting  cells 
are  found  among  the  epithelial  elements  in  this  region,  and 
groups  of  cells  are  enclosed  by  dense    connective    tissue. 


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8 


Fig.  57. 

Section  of  the  pars  posterior  of  the  lemur  (lemur  caita),  showing  apparent 
islets  of  pars  intermedia  cells  in  the  pars  nervosa. 

X  250. 

The  pars  anterior  in  the  animal  under  consideration  shows 
most  pronounced  and  interesting  features.  The  eosinophil  ele- 
ments are  very  bright  and  prominent,  and  in  places  are  arranged 
in  branching  columns  after  the  manner  of  heart-muscle.  The 
only  other  type  of  cell  seen  is  the  active  chromophobe  cell 
(fig.  58).  These  chromophobe  cells  are  large,  stain  very  faintly 
with  basic  dyes,  and  appear  to  be  almost  confluent  in  places. 
This  pseudosyncytial  appearance  of  chromophobe  cells  was  first 
described  by  Lannois  and  Mulon1  as  occurring  in  pregnancy  ;   it 

1  Lannois,  P.  E.,  and  P.  Mulon,  Compt.  Rend,  de  Soc.  Biol,  1903,  i,  448. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     15 

is   also   seen   in   pathological   conditions — notably  after    removal 
of  the  thyroid — indeed,  plate  4  (facing  p.  187),  showing  the  effect 

W$B&$*  . ■'.. * >    "- l/° -^  ° » 
."  ■--  £*   i^   "-   °    « vi 


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Fig.  58. 

.Section  of  the  pars  anterior  of  the  lemur  (lemur  catta),  showing  dark  eosinophil 
cells  and  light  chromophobe  cells. 

X250. 

on  the  pars  anterior  in  the  cat  of  experimental  removal  of  the 
thyroid,  almost  illustrates 
the  normal  appearance  seen 
in  the  lemur  examined, 
which  was  a  young  non- 
pregnant female.  This  phe- 
nomenon is  curious  when 
considered  in  conjunction 
with  what  has  already  been 
said  about  the  structure  of 
the  thyroid  in  this  animal. 

Simiidce.  — -  In    monkeys  FlG-  59- 

the    pituitary   is   situated    in        Median  sagittal  section  of  the  pituitary 
a    deep    fossa;     it   is,   there-  oi  the  monkey  (macacus  rhesus). 

fore,  roundly  oval  in  shape, 

and   the    pars   nervosa   is   posterior   in   position   (fig.    .V.)).      It    is 


76  MORPHOLOGY 

probable  that  the  pituitaries  of  the  different  species  are  very 
similar.  I  have  examined  macacus  rhesus.  Herring1  and  Tilney2 
also  have  examined  this  organ  in  monkeys.  Tilney  examined 
the  baboon  (cynocejjhalus  babuin),  but  Herring  does  not  state  the 
species  described  by  him. 

The  pars  intermedia  forms  an  investment  varying  in  depth, 
but  usually  thin,  over  the  front  and  sides  of  the  pars  nervosa 
and  along  the  front,  and,  in  some  cases,  around  the  stalk. 

The  pars  nervosa  is  solid,  and  is  comparatively  large  (fig.  59). 

The  pars  anterior  appears  to  be  composed  chiefly  of  eosino- 
phil cells,  although   some   faintly  basic   staining — really  chromo- 


Fig.  60. 
Median  sagittal  section  of  the  human  pituitary. 


X5. 


phobe — cells  may  be  seen.  My  observations  coincide  with  those 
of  Herring  rather  than  with  those  of  Tilney,  in  regard  to  the 
absence  of  basophils  ;  but  this  may  be  explained  by  the 
fact  that  Herring  and  I  examined  the  same  species,  while 
Tilney  examined  a  species  that  may  differ  from  macacus  rhesus. 
Blood-spaces  are  numerous,  but  there  is  little  other  supporting 
tissue.  The  cleft  is  very  narrow,  and  in  this  respect  and  in  the 
limitation  of  the  pars  intermedia  the  pituitary  of  the  monkey 
approaches  in  appearance  that  seen  in  Man  (fig.  60),  in  whom 
the  pars  intermedia  is  of  very  slight  extent,  as  already  described. 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 

2  Tilney  F.,  Memoirs  Wistar  Instil  Anal  ami  Biol,  Philadelphia,  1911  (No.  2),  1. 


COMPARATIVE   ANATOMY   OF   THE   PITUITARY     77 

In  this  brief  study  of  the  comparative  features  of  the 
pituitary  a  few  facts  stand  out  as  being  of  considerable  im- 
portance. Their  importance  is  related  to  the  elucidation  of  the 
physiological  functions  of  this  organ. 

We  have  found  in  one  of  the  lowest  vertebrates  the  complete 
absence  of  a  pars  nervosa  ;  we  have  observed  its  sudden  develop- 
ment to,  apparently,  an  organ  of  considerable  physiological  signific- 
ance, if  we  may  attach  functional  importance  to  morphological 
structure,  which  is,  however,  always  a  dangerous  procedure.  In 
bony  fishes  the  maximum  surface  of  nervous  tissue  is  exposed, 
by  a  series  of  branching  processes,  to  the  epithelial  covering  ; 
and  this  phenomenon  obtains  to  a  considerable  extent  in  reptiles 
and  even  in  the  monotreme  mammals.  Then,  apparently,  this 
feature  disappears,  except  for  the  evidence  of  epithelial  ingrowths 
in  the  pars  nervosa,  such  as  are  seen  in  the  cat  and  lemur.  In  the 
opossum  and  in  the  cat  we  find  another  interesting  morphological 
characteristic,  namely,  a  cavity  within  the  pars  nervosa  which 
is  continuous  with  the  third  ventricle  ;  and  this  has  been 
held  by  Herring1,  dishing2  and  others  to  constitute  a  factor  of 
prime  importance  from  a  physiological  point  of  view.  In  the 
amphibians  and  ungulates  we  have  seen  that  blood-vessels  are 
very  numerous  in  connexion  with  the  pars  posterior.  This,  too, 
may  be  a  point  of  some  moment  in  regard  to  the  physiology  of 
this  part  of  the  pituitary. 

We  have,  moreover,  observed  that  the  histological  evidence 
of  activity  of  the  pars  intermedia  differs  in  different  mammals, 
and  that  it  appears  to  be  greatest  in  the  cat  and  dog  so  far  as 
the  actual  production  of  an  obvious  secretion  is  concerned.  In 
the  monkeys  and  in  Man  the  pars  intermedia  and  the  pars 
nervosa  appear  to  be  of  small  significance. 

The  comparative  structure  of  the  pars  anterior  likewise 
affords  us  some  food  for  reflexion.  In  certain  fishes  and  reptiles 
the  cells  are  arranged  in  acini  with  blood-vessels  in  the  lumina 
— a  disposition  which  facilitates  the  passage  of  the  secretion  of 
the  cells  directly  into  the  blood-stream.  In  no  case  do  we  see 
quite  so  well-defined  a  differentiation  in  eosinophils,  basophils 
and  chromophobes  as  in  the  normal  pituitary  of  Man.  There 
is,  however,  no  doubt  that  in  the  lower  vertebrates  differentia- 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121,  161. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


78  MORPHOLOGY 

tions  do  exist,  but  they  are  not  pronounced  in  most  of  the 
mammals,  nor,  indeed,  in  Man  till  puberty.  In  the  lemur 
there  are  extremely  interesting  histological  features  which  we 
shall  discuss  again  later,  for  use  will  be  made  of  this  compara- 
tive study  in  discussing  the  peculiar  problems  associated  with 
the  physiology  and  pathology  of  the  pituitary. 


PART    II 

THE    PHYSIOLOGY 

OF 

THE    PITUITARY 


PART   II 
THE    PHYSIOLOGY   OF  THE   PITUITARY 

In  order  to  obtain  information  concerning  the  normal  func- 
tions of  an  organ,  we  have  definite  and  well-recognized  methods 
of  investigation.  These  are  either  purely  physiological  or  patho- 
physiological ;  and  before  proceeding  to  discuss  the  application 
of  them  to  the  study  of  the  pituitary  body  it  will  be  useful  to 
summarize  the  methods  themselves. 

I.   Physiological  Methods 

(a)  Histological  investigations.- — These  enlighten  us  as  to 
the  nature  of  the  structure  with  which  we  have  to  deal,  and 
also  enable  us  to  discern  the  character  of  its  functional  processes 
in  various  circumstances.  We  learn  by  differential  staining  the 
chemical  affinities  of  the  different  cells  of  the  tissues  investigated, 
and  the  various  phases  of  their  activity. 

{b)  Chemical  examination  of  the  body-tissues  and  excreta. 
— By  this  means  we  are  sometimes  able  to  discover  the  chemical 
nature  of  a  secretion,  and  to  trace  in  the  blood  or  other  body- 
fluids  its  rate  of  production  and  disappearance. 

By  this  method,  also,  we  are  able  to  observe  changes  in  the 
metabolism. 

(c)  Injection,  absorption,  and  ingestion  experiments. — 
In  these  investigations  extracts  of  the  organ  concerned  are  in- 
troduced into  the  body  of  the  experimental  subject,  and  obser- 
vations are  then  made  in  the  following  ways  in  regard  to  the 
immediate  and  remote  effects  produced. 

i.  Immediate  effects  of  injections  are  noted  by  means  of 
various  physiological  recorders  ;  of  absorption  by  placing 
the  structures  to  be  tested  in  Ringer's  solution  contain- 
ing the  extract,  and  by  means  of  the  implantation  of 
freshly  excised  organs. 


80  PHYSIOLOGY 

ii.  Late  effects  of  daily  injections  or  ingestions  into  a  pre- 
viously normal  animal,  are  noted  in  regard  to  the  meta- 
bolism and  to  the  structure  of  various  other  organs. 

It  is  generally  conceded  that  these  methods  of  investigation 
are  open  to  few  objections  ;  but  we  must  bear  in  mind  that  in 
our  experiments  under  the  third  heading  we  are  usually  ex- 
hibiting quantities  of  an  organic  extract  considerably  in  excess 
of  those  which  the  animal  could  receive  from  the  same  organ  in 
normal  circumstances  and  in  the  same  period  of  time. 

II.  Pathophysiological  methods 

(a)  Operative  procedures. — i.  Partial  or  complete  extirpation, 

destruction  or  injury  of  the  organ  in  situ. — -There  is  no 
doubt  that  partial  or  complete  extirpations  are  greatly  to 
be  preferred  to  destruction  with  the  cautery  and  with 
other  agents  ;  for  it  is  difficult  with  destructive  methods 
to  limit  the  amount  of  necrosis  effected,  or  to  estimate 
the  damage  done  to  adjacent  portions  of  the  organ  and 
the  surrounding  tissues.  By  extirpation  experiments  we 
are  able  to  produce  cessation  of,  or  insufficiency  in,  the 
functions  of  an  organ. 

ii.  Extirpation  or  destruction  follozved  by  substitution  therapy 
by  means  of  injections,  feeding,  or  grafting. — By  these 
means  we  are  often  able  to  learn  whether  our  deductions, 
based  on  extirpation  or  destruction  alone,  are  correct,  for 
substitution  may  mitigate  the  effects  produced.  By  this 
method  of  investigation,  however,  positive  results  alone 
are  of  value. 

iii.  Stimulation  of  the  organ  in  situ. — This  is  accomplished  by 
electrical  impulses  applied  indirectly  through  the  func- 
tional nerves,  or  by  electrical  currents  or  other  methods 
of  irritation,  such  as  the  pressure  of  a  foreign  body, 
applied  directly  ;  also,  by  the  injection  of  exciting  sub- 
stances (hormones)  into  the  circulation. 

(b)  Removal  of,  or  injury  to,  correlated  organs. — In  this 
way  we  may  become  acquainted  with  the  relationships  between 
various  structures,  such  as  the  organs  of  internal  secretion. 

(c)  Injection  of  bacteria  or  toxins  into  the  blood-stream, 


PHYSIOLOGY   OF   THE   PITUITARY  81 

peritoneal  cavity  or  subcutaneous  tissues. — By  this  method, 
which,  possibly,  is  a  form  of  stimulation,  we  learn  the  behaviour 
of  the  organ  to  infections  or  toxaemias — a  matter  requiring 
consideration  apart  from  stimulation  by  hormones. 

(d)  Interpretation  of  pathological  processes  affecting  the 
normal  physiology  of  the  organ  concerned.— Many  patho- 
logical processes  in  an  organ  give  rise  to  excessive  or  diminished 
function  in  varying  degrees.  From  these  so-called  '  experiments 
of  Nature  '  the  physiologist  may  find  much  evidence  to  support 
or  disprove  conclusions  reached  in  other  ways. 

In  these  methods,  then,  if  they  be  properly  carried  out,  we 
have  the  means  of  investigating  fairly  completely  the  functions 
of  an  organ  such  as  the  pituitary  body.  It  will  be  obvious, 
moreover,  that  sometimes  combined  experiments,  such  as  those 
described  above  under  II  (a)  ii,  may  be  especially  useful ; 
and  in  this  connexion  it  must  be  pointed  out  that  the  full  ap- 
preciation of  the  results  of  many  of  the  methods  mentioned 
depends  on  the  completeness  of  the  investigation.  For  instance, 
in  extirpation  experiments  we  must  not  be  satisfied  with  ob- 
serving whether  the  animal  dies  or  survives  ;  we  must  learn,  if 
possible,  the  actual  effect  of  the  experiment  on  the  correlated 
organs  and  structures,  and  on  the  metabolism  generally.  Un- 
fortunately, this  completeness  of  investigation  is  rarely  possible 
to  the  ordinary  investigator,  for  he  is  not  usually  an  expert  in 
surgery,  histology,  chemistry  and  general  medicine,  and  at  the 
same  time  able  to  devote  his  whole  time  to  experimental  work ; 
and,  on  the  other  hand,  the  pure  physiologist  is  not  always 
sufficiently  acquainted  with  the  technique  of  surgery,  and  with 
the  possible  applications  of  his  results  to  medical  and  surgical 
practice.  It  is,  therefore,  at  present  only  by  combining  the 
results  of  many  workers  that  we  are  able  to  view  a  subject 
such  as  that  which  we  are  at  present  discussing  from  a  more 
or  less  comprehensive  standpoint.  No  doubt  the  time  will  come 
when  hospital  laboratories  will  be  established  in  this  country 
in  which  complete  investigations  can  be  carried  out  under  the 
same  roof  by  the  combined  efforts  of  many  workers,  each  of 
whom  is  a  specialist  in  his  own  sphere  of  action. 


PHYSIOLOGICAL   INVESTIGATIONS 


HISTOLOGICAL     OBSERVATIONS 

In  its  histological  features  the  pituitary  body  is  one  of  the  most 
puzzling  structures  in  the  animal  organism.  It  has,  therefore, 
been  the  subject  of  much  careful  study  ;  and  however  imper- 
fectly we  can  connect  the  physiological  functions  with  the  special 
structure,  we  are  at  least  now  thoroughly  familiar  with  the  latter 
in  the  human  adult.  Nevertheless,  a  careful  investigation  into 
the  differences  seen  at  the  different  periods  of  life  is  urgently 
needed  ;  for,  although  it  may  be  possible  for  an  experienced 
observer  to  recognize  the  pituitary  of  the  child  by  the  com- 
parative uniformity  in  the  staining  reactions  of  the  cells  of  the 
pars  anterior,  and  that  of  elderly  persons  by  the  amount  of  pig- 
ment found  in  the  pars  nervosa,  these  distinctions  are  only  rough 
and  approximate.  So,  too,  further  observations  concerning  the 
structural  alterations  associated  with  various  physiological  and 
pathological  conditions  are  required  before  we  can  completely 
understand  the  significance  of  such  changes. 

The  general  structure  and  the  relationship  of  the  different 
portions  of  the  pituitary  have  already  been  described.  The 
same  combination  of  the  parts  is  common  to  all  mammals,  with 
slight  differences  in  regard  to  the  extent  of  the  pars  anterior, 
the  differentiation  of  the  cells  of  the  pars  intermedia,  the  solidity 
or  hollowness  of  the  pars  nervosa,  and  the  relation  of  this  nerv- 
ous process  to  the  epithelial  portions.  The  pars  nervosa  always 
directly  underlies  the  third  ventricle,  and  this,  as  we  shall 
see,  has  been  held  to  be  a  matter  of  some  importance  in  con- 
nexion with  the  pathology  as  well  as  the  physiology  of  the 
pituitary.  We  have  seen,  too,  that  in  most  animals  and  in 
the  human  subject  the  anterior  lobe  is  separated  by  a  cleft 
(the  original  cavity  of  Rathke's  pouch)  from  the  posterior  lobe. 


HISTOLOGICAL   OBSERVATIONS  83 

Having  thus  got  our  bearings  we  may  proceed  to  an  ex- 
amination of  the  different  parts  of  the  pituitary  under  high 
magnifications  in  order  to  determine  the  connexions  of  the 
various  elements  with  the  functions  of  the  organ  as  a  whole. 
It  will  be  remembered  that  each  part — the  pars  anterior,  the 
pars  intermedia  and  the  pars  nervosa — presents  specific  and  dis- 
tinct morphological  characteristics  ;  so  it  will  be  advisable  to 
consider  them  separately,  in  spite  of  the  fact  that  the  pars 
anterior  and  the  pars  intermedia  have  a  common  origin. 

Pars  anterior — As  already  described,  this  portion  of  the 
pituitary  is  composed  of  epithelial  cells  arranged  in  a  more  or 
less  branching  or  tubular  fashion.  Granular  secretion  may  be 
seen  in  the  lumen  of  the  acini  (fig.  18,  p.  30)  or  in  the  blood- 
sinuses  which  are  large  and  numerous.  It  is,  therefore,  believed 
that  the  secretion  of  the  pars  anterior  is  poured  directly  into 
the  blood-stream  or  stored  in  the  form  of  colloid.  We  have 
noted,  too,  that  in  adults  among  the  higher  animals  the  epithelial 
cells  of  the  pars  anterior  show  differential  staining  affinities,  in 
consequence  of  which  the  various  types  have  been  described  as 
being  chromophil  and  chromophobe — they  stain  well  or  indiffer- 
ently. Of  the  chromophil  cells  some  are  acidophil  and  show 
considerable  avidity  for  eosin,  while  others  are  basophil  and  stain 
deeply  with  hsematoxylin.  The  chromophobe  cells  are  tinged 
very  lightly  with  basic  dyes  (plate  1,  facing  p.  30).  Many  in- 
vestigators have  sought  to  place  these  different  types  of  cells  in 
regular  situations  in  the  anterior  lobe  ;  but,  beyond  the  facts 
that  the  basophils  are  most  numerous  at  the  periphery  and  that 
the  eosinophils  surround  the  blood-sinuses,  there  seems  to  be 
little  justification  for  such  descriptions,  and  my  own  experience 
is  that  no  two  pituitaries  in  any  animal  or  human  being  are 
alike  in  this  respect. 

There  are  certain  important  normal  histological  phenomena 
associated  with  physiological  states,  which  require  special  con- 
sideration. 

Pregnancy. — Comte1  first,  and  later  Erdheim  and  Stumme2, 
noticed  that  in  pregnancy  the  anterior  lobe  enlarges  considerably. 

1  Comte,  L.,  Zeiglers  Beitr.  z.  Pathol  Anal.  u.  z.  Allg.  Pathol.,  1898,  xxiii,  90. 

2  Erdheim,  J.,  and  E.  Stumme,  Zeighr's  Beitr.  z.  Pathol.  Anaf.  %i.  z.  Allg.  Pathol., 
1909.  xlvi.  1. 


84 


PHYSIOLOGY 


I 


(V 


*      % 


•4 


• 


Fig.  61. 

Section  of  the  pars  anterior  of  the  pregnant  rabbit,  showing  eosinophilia 
of  the  cells.     (Photomicrograph.) 


m 


i     „ 


X500. 


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fc! 


Fig.  62. 

Section  of  the  pars  anterior  of  the  pregnant  rabbit,  showing  large  chromophobe 
('pregnancy')  cells.     (Photomicrograph.) 

X  500. 


HISTOLOGICAL   OBSERVATIONS  85 

This  increase  in  size  is  stated  by  Erdheim  and  Stumme  to  be 
due  entirely  to  changes  in  the  chromophobe  ('  neutrophil ', 
'  principal ',  or  '  chief  ')  cells,  which  now  develop  and  become 
slightly  more  chromophil  ('  pregnancy  cells  ') ;  that  is  to  say, 
there  is  during  pregnancy  a  condition  of  excessive  activity  in 
regard  to  these  cells.  Siguret1  observed  in  rabbits  a  diminution 
in  the  number  of  the  chromophobe  cells  and  an  increase  in  the 
number  of  eosinophil.  This  author  also  found  that  the  change 
was  as  marked  at  the  commencement  as  at  the  end  of  gesta- 
tion. Lannois  and  Mulon2  were  the  first  to  describe  the  con- 
fluence of  the  chromophobe  cells  in  pregnancy,  and  this  they 
designated  '  syncytial'. 

My  own  observations  have  impressed  me  with  the  fact  that 
considerable  variations  may  be  found  during  pregnancy  both  in 
animals  and  women.  Usually  in  rabbits  there  is,  as  Siguret  has 
stated,  an  increase  in  the  degree  of  eosinophilia — that  is  to  say, 
the  lightly  stainiig  eosinophil  cells,  which  predominate  in  the 
pars  anterior  of  this  animal,  stain  more  deeply  (fig.  61).  Never- 
theless, I  have  seen  extremely  pronounced  chromophobia  in  this 
situation  during  pregnancy  in  the  rabbit  (fig.  62).  In  women 
the  chromophobe  cells  are  usually  plentiful  in  these  circum- 
stances, but  this  is  not  always  the  case. 

The  essential  change,  however,  in  the  pars  anterior  of  all 
animals  during  pregnancy  is  towards  greater  activity,  and  this 
may  be  represented  by  increased  eosinophilia  of  the  epithelial 
elements  or  by  chromophobia.  The  chromophobe  cells  in  these 
circumstances  often  assume  a  lobulated  or  an  adenomatous 
arrangement  (figs.  63  and  64). 

Hibernation,  too,  produces  striking  changes  in  the  histological 
appearances  of  the  pituitary,  and  these  occur  in  the  epithelial 
elements  of  the  partes  anterior  and  intermedia — the  secretory 
cells  of  this  organ. 

Gemelli3  first  called  attention  to  this  phenomenon,  and  lie 
came  to  the  conclusion  that  hibernation  is  a  condition  of 
pluriglandular  inactivity.  He  found  in  the  pars  anterior  that 
the  cells  arc  entirely  undifferentiated  in  this  physiological 
state. 

1  Siguret,  A.,  Llhypo2)hyse  pendant  la  gestation,  Paris,  1912. 

2  Lannois,  P.  E.,  and  P.  Mulon,  Compt.  Rend.  Soc.  de  Biol,  1903,  i,  448. 

3  Gemelli,  A.,  Arch.  p.  le  Sci.  Med.,  190G,  xxx,  341. 


86 


PHYSIOLOGY 


.?#e 


Fig.  63. 

Section  of  the  pars  anterior  of  the  pregnant  guinea-pig,  showing  the  tabulated 
arrangement  of  chromophobe  cells.     (Photomicrograph.) 

X  250. 


ft' 
'i 


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■ 


Fig.  64. 

Section  of  the  pars  anterior  of  the  pregnant  woman,  showing  the  tabulated 
arrangement  of  chromophobe  cells.      (Photomicrograph.) 

X  125. 


HISTOLOGICAL   OBSERVATIONS  87 

Cushing  and  Goetsch1  came  to  a  similar  conclusion  regarding 
the  condition  of  the  pituitary  during  hibernation.  Further, 
these  observers  have  suggested  that  physiological  sleep  may  be 
associated  with  temporary  inactivity  of  the  pituitary.  In  sup- 
port of  this  hypothesis  they  refer  to  the  torpor  usually  seen  in 
animals  from  which  a  large  portion  of  the  pars  anterior  has 
been  removed,  and  to  the  drowsiness  seen  in  advanced  pituitary 
disease  associated  with  diminished  secretion — that  is,  in  the 
syndrome  dystrophia  adiposogenital.  They  have  called  par- 
ticular attention  to  a  case  of  pituitary  tumour  in  which  the 
patient  became  comatose  and  had  a  low  body-temperature. 
Cushing  operated  and  found  a  cyst  in  the  pars  anterior  which 
he  evacuated.  There  was  no  general  intracranial  pressure. 
Pituitary  extract  made  from  the  whole  gland  improved  the 
condition,  and  permanent  relief  was  obtained  by  the  implant- 
ation of  the  pars  anterior  from  a  stillborn  child  into  the 
subcortical  tissue  of  the  brain  of  the  patient. 

Whatever  changes  occur  elsewhere,  there  is  no  doubt  that 
definite  alterations  are  found  in  the  pituitary  during  hibernation. 
In  the  hedgehog  and  dormouse,  which  I  have  examined, 
during  the  summer  the  cells  of  the  partes  anterior  and 
intermedia  are  active — they  are  swollen  and  blurred,  and  the 
nuclei  stain  faintly  (fig.  65a)  ;  but  during  the  period  of 
winter-sleej^  they  become  shrunken  and  discrete,  and  their 
nuclei  stain  deeply  (fig.  65b).  Associated  with  these  changes  in 
the  hibernating  animal  there  is  an  enormous  deposition  of  fat 
—just  as  there  may  be  in  experimentally  produced  or  patho- 
logical insufficiency  of  the  pituitary  secretion  :  I  have  seen  the 
subcutaneous  layer  of  fat  in  the  hibernating  hedgehog  one  inch 
in  thickness. 

Brooding  in  hens,  as  already  indicated  (p.  53),  is  associated 
with  varying  degrees  of  pituitary  insufficiency  that  can  be 
recognized  histologically.  In  the  non-laying  hen  that  is  not 
brooding  the  pituitary  appears  less  active  than  that  of  the  laying 
hen,  but  more  active  than  that  of  the  brooding  hen.  The  adult 
cock's  pituitary  resembles  that  of  the  laying  hen.  Observations 
concerning  these  physiological  variations  in  hens  do  not  appear 
to  have  been  recorded  previously.  I  have  been  unable  to 
conduct  my  investigations  on  a  large  scale  at  the  present  time, 
1  Cushing,  H.,  and  E.  Goetsch,  Journ.  Exper.  Med.,  1915,  xxii,  2~>. 


88  PHYSIOLOGY 


J    j  ?'*»',  *$     ft 

^  °0  'J  ', 


•J?s  JK-^V 


pa 


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Fig.  65a. 


Section  of  the  pituitary  of  the  normal  non-hibernating  hedgehog,  showing  the 
distal  epithelium  on  the  right  and  the  juxtaneural  epithelium  covering  the  pars 
nervosa  on  the  left. 

X  125. 


ft*        «^        *','»'        *'*       " 

V  *«  •*  s».  ??X*.  '>:-.•*» 5J-i 


Fig.  65b. 

Section  of  the  pituitary  of  the  hibernating  hedgehog,  showing  the  inactive 
shrunken  cells  of  the  distal  epithelium  on  the  right,  and  of  the  juxtaneural 
epithelium  on  the  left. 

X  125. 


HISTOLOGICAL   OBSERVATIONS  89 

but  there  appeared  to  be  no  doubt  whatever  as  to  the  cause  and 
effect  in  the  birds  examined. 

In  the  pars  anterior  of  the  laying  hen  there  are  many  large 
eosinophil  cells,  mixed  with  chromophobe  cells  in  an  irregular 
manner ;  and  the  cells  look  blurred  and  swollen  (fig.  66a).  In 
the  brooding  hen  the  cells  are  almost  all  small  and  chromophobe ; 
they  appear  shrunken  and  inactive,  and  they  form  definite  acini, 
many  of  which  contain  granular  secretion,  enclosed  in  a  con- 
nective tissue  meshwork  (fig.  66b). 

The  appearances  of  the  pituitary  in  these  physiological  states 
— pregnancy,  hibernation  and  brooding — throw  much  light  on 
the  normal  physiology  of  the  pituitary  in  relation  to  its  struc- 
ture ;  but  it  is  improbable  that  this  organ  alone  is  affected  in 
these  circumstances.  Gemelli's  statement  that  hibernation  is 
pluriglandular  in  origin  is  probably  correct  ;  and  we  know  that 
all  the  organs  of  internal  secretion  are  altered  during  the  period 
of  gestation,  so  it  is  probable  that  brooding  also  is  associated 
with  pluriglandular  inactivity. 

It  is  a  little  more  difficult  to  deduce  facts  of  physiological 
import  from  the  comparative  morphology  of  the  pars  anterior 
of  the  pituitary,  and  we  must  reserve  some  of  the  points  worthy 
of  consideration  for  a  short  discussion  later  of  the  comparative 
physiology  of  this  organ.  It  may,  however,  be  mentioned  that 
among  the  mammals  we  find  considerable  variation  in  tinctorial 
affinities.  In  the  ornithorhynchus  all  varieties  of  cells  are 
found  in  the  pars  anterior,  and  especially  wc  may  observe 
several  stages  in  the  formation  of  the  deeply  staining  basophil 
cells.  In  the  rodents,  such  as  the  rabbit,  true  basophils  are 
very  rare,  and  in  no  animal  below  the  monkey  have  I  observed 
basophil  colloid.  This  is  a  matter  of  some  interest,  and  it 
probably  explains  the  fact  that  eosinophilia  is  the  most  im- 
portant phase  of  activity  in  these  animals. 

We  are  now  in  a  position  to  consider  the  significance  of  the 
different  types  of  cells  found  in  the  pars  anterior.  There  is 
some  divergence  of  opinion  on  this  question,  and  two  views  are 
held  :  first,  some  authorities,  of  whom  Gcmelli1  is  the  chief 
advocate,  believe  that  the  different  types  of  cells  have  different 
functions;  second,  there  are  many  who  think  with  Saint-Remy2 

1  Gemelli,  A.,  Folia  Neurobiol,  1908,  ii,  167. 

2  Saint-Remy,  G.,  Compl.  Rend,  de  V Acad,  des  Sci.    1892, cxiv,  770. 


90  PHYSIOLOGY 


Fig.  66a. 

Section  of  the  pars  anterior  of  the  laying  hen,  showing  large  eosinophil  cells  mixed 
indiscriminately  with  chromophobe  cells. 

X  125. 


-   -     .  , 


•     » 


Fig.  66b. 

Section  of  the  pars  anterior  of  the  brooding  hen,  showing  shrunken  chromophobe 
cells  divided  into  acinous  groups  by  connective  tissue. 

X  125. 


HISTOLOGICAL   OBSERVATIONS  91 

and  Benda1  that  the  apparently  different  types  of  cells  represent 
the  same  structure  in  different  stages  of  activity. 

As  this  is  a  point  of  considerable  interest  and  importance, 
as  well  as  of  doubt,  I  shall  state  my  own  views  on  the 
subject. 

In  general,  my  observations  lead  me  to  support  the  second 
view ;  and  I  feel  able  to  put  my  conclusions  into  a  more 
definite  form  than  has  hitherto  been  attempted. 

In  the  first  place  it  must  be  emphasized  that  in  no  part  of 
the  anterior  lobe  in  normal  circumstances — excluding  pregnancy, 
brooding,  and  hibernation — can  one  find  positive  evidence  of  the 
presence  of  any  one  type  of  cell  to  the  exclusion  of  the  others ; 
that  is  to  say,  at  the  most  important  points  of  observation 
all  varieties  are  seen  to  be  mingled  together  (plate  1,  facing 
p.  30).  This  fact  alone  is  significant,  for  it  is  what  one  would 
expect  to  find  where  different  stages  of  secretory  activity  are 
in  progress  at  the  same  time  ;  and  it  appears  to  me  to  dispose 
of  Erdheim's2  argument  for  the  opposite  view,  namely,  that  cells 
of  the  same  kind  may  be  found  in  clusters  in  abnormal  circum- 
stances. 

With  regard  to  the  disposal  of  the  secretion  of  the  anterior 
lobe,  it  appears  that  for  the  most  part  this  is  carried  away  in 
the  blood-channels.  Thaon3  and  others  have  drawn  attention 
to  the  fact  that  granular  secretion  may  actually  be  seen  within 
the  blood-sinuses.  Nevertheless,  there  can  be  little  doubt  that 
the  secretion  is  chiefly  taken  into  the  blood-stream  in  infinit- 
esimal quantities.  In  exceptional  circumstances,  however — 
influenced,  no  doubt,  by  metabolic  conditions — the  secretion  is 
stored.  This  storage  secretion,  unlike  the  normal  thyroid  secre- 
tion4, usually  stains  with  haematoxylin  (basophil)  rather  than 
with  eosin  (acidophil),  although  abnormally  an  acidophil  affinity 
is  sometimes  seen.  The  secretion  has  a  granular  appearance 
when  eosinophil  or  neutrophil,  and  only  resembles  homogeneous 
colloid  when  distinctly  basophil.  This  basophil  affinity  of  the 
formed   colloid    secretion  gives   us   valuable   evidence   as  to  the 

1  Benda,  C,  Berl.  Klin.  Woch.,  1900,  xxxvii,  1205. 

2  Erdheim,  J.,  Frankf.  Zeilschr.  f.  Pathol,  1910,  iv,  70. 

3  Thaon,  P.,  L'hypophyse,  Pans,  1907. 

4  It  should  be  stated,  however,  that  thyroid  secretion  may,  in  apparently 
normal  circumstances,  show  a  faintly  basophil  tendency. 


92  PHYSIOLOGY 

parts  played  by  the  different  cells  in  regard  to  the  secretory 
products  of  the  pars  anterior. 

In  attempting  to  describe  the  secretory  phases  I  shall  con- 
sider first  the  eosinophil  cells.  These  cells  are  the  elements 
which  produce  the  internal  secretion  of  the  pars  anterior  in 
normal  circumstances.  It  is  possible  to  observe  differing  degrees 
of  staining  affinity  in  various  eventualities,  and  always  it  is 
the  granules  within  the  cells  that  stain  most  deeply.  The 
eosinophil  cells  lie  against  the  walls  of  the  blood-channels,  and 
their  secretion  is  taken  up  by  the  blood-stream.  If  the  secre- 
tion is  not  removed  from  these  cells,  chemical  changes  occur 
which  alter  the  tinctorial  affinities  of  the  secretory  products  : 
gradually  the  acidophilia  diminishes,  and  basophilia,  at  first 
slight,  becomes  more  and  more  pronounced  until  the  typical, 
darkly  staining,  basophil  cell  is  produced. 

It  will  be  remembered  that  in  the  eosinophil  cell  the  nucleus 
is  central  and  is  surrounded  by  an  extensive  cytoplasm  con- 
taining eosinophil  granules,  and  that  in  the  deeply  basophil  cell 
the  nucleus  is  eccentric. 

Several  phases  may  be  observed  in  the  basophils  :  first,  they 
are  translucent  and  contain  granules  ;  later,  they  become 
opaque  and  homogeneous,  and  in  the  transition  the  nucleus  is 
gradually  displaced  to  the  periphery  of  the  cell.  Eventually,  the 
basophil  cell  disgorges  dark  basophil  colloid.  This  colloid  is 
surrounded  by  cells  most  of  which  are  small  chromophobe  ele- 
ments with  large  clear  nuclei  and  little  cytoplasm — the  exhausted 
remains,  in  fact,  of  the  basophils  that  have  extruded  their  colloid 
material  (fig.  67).  These  chromophobe  cells  regenerate,  and 
in  normal  circumstances  become  eosinophil,  and  pour  their 
secretion  into  the  blood-vessels  ;  or  they  change  once  more  into 
the  basophil  cells,  and  store  their  secretion  until  such  time  as 
again  they  extrude  it  in  the  form  of  colloid.  In  those  cases  in 
which  there  is  an  immediate  and  urgent  demand  for  the  secre- 
tion of  the  pars  anterior,  as  in  pregnancy,  the  small  chromophobe 
cells,  and  even  some  of  the  young  eosinophils,  increase  in  size 
but  remain  chromophobe,  and  yield  up  their  secretion  as  soon 
as  it  is  formed  ;  indeed,  it  is  not  unusual  to  see  bubble-like 
collections  of  secretion  among  the  cells,  especially  in  abnormal 
circumstances,  such  as  occur  after  removal  of  the  thyroid. 

The  phases  just  described  may  be  summarized  in  a  few  words  : 


HISTOLOGICAL   OBSERVATIONS 


93 


the  small  chromophobe  cells  are  exhausted  cells  ;  the  eosino- 
phil cells  are  the  active  secretory  cells  in  normal  circumstances  ; 
the  basophil  cells  form  a  storage  secretion ;  and  the  large  chromo- 
phobe cells,  which  develop  from  the  small  exhausted  chromo- 
phobe cells  or  the  young  eosinophils,  are  formed  only  when  there 
is  an  urgent  and  immediate  need  for  the  secretion  of  the  pars 
anterior. 


fY- 


Fig.  67. 

Section  of  the  normal  human  pars  anterior,  showing  basophil  colloid  surrounded  by 
chromophobe  cells,  one  or  two  of  which  are  becoming  eosinophil.    (Photomicrograph.) 

X500. 

Thaon1,  Erdheim  and  Stumme2  and  others  have  directed 
attention  to  the  lipoid  particles  that  may  be  demonstrated  in 
the  epithelial  elements  of  the  pituitary.  These  bodies  stain 
with  sudan  III,  scharlack  R  and  osmic  acid.  They  are,  of  course, 
soluble  in  ether  and  alcohol. 

My  own  material  is  not  sufficient  from  which  to  draw  con- 
clusions, but  there  can  be  no  doubt  that  the  amount  of  lipoid 
material  demonstrated  by  staining  methods  varies  enormously 
in  different  pituitaries,  and  probably  in  different  circumstances. 

1  Thaon,  P.,  L'hypophyse,  Paris,  1907. 

2  Erdheim,  J.,  and  E.  Stumme,  Zeigler's  Beitr.  z.  Pathol.  Anal.  u.  z.  Allg. 
Pathol.  1909.  xlvi,  1. 


94  PHYSIOLOGY 

In  some  the  amount  is  large  (fig.  68) ;  in  others  there  is  very- 
little.  The  stained  lipoid  bodies  vary  in  size  from  dust-like 
particles  to  globular  masses  considerably  larger  than  the  nuclei 
of  the  cells.  I  have  been  unable  to  detect  lipoid  substances  in 
the  granular  secretion  found  in  the  acini. 

According  to  Erdheim  and  Stumme,  chromophobe  cells — 
including  pregnancy  cells — are  poor  in  lipoids,  while  the  chromo- 
phils — that  is  to  say,  eosinophils  and  basophils — may  contain 
large  quantities  of  these  substances.     But  in  my  experience  the 


Fig.  68. 

Section  of  the  normal  human  pars  anterior  stained  with  osmic  acid,  showing 
lipoids  in  the  cells.     (Photomicrograph.) 

X  125. 

lipoids,  as  made  evident  by  staining  methods,  vary  in  quantity, 
even  in  cells  of  the  same  character  ;  consequently  I  feel  that 
we  are  not  in  the  possession  of  enough  information  to  draw 
satisfactory  conclusions  as  to  their  exact  nature  and  import. 

The  fact  that  there  are  sympathetic  nerves  in  the  pars 
anterior  is  probably  of  significance  from  a  functional  point  of 
view. 

Pars  intermedia. — -As  already  indicated,  this  portion  of  the 
pituitary   is   derived  from    the    pouch    of   Rathke    and  becomes 


HISTOLOGICAL   OBSERVATIONS  95 

slightly  differentiated  from  the  rest  of  the  anterior  lobe  with 
which  it  is  continuous.  For  the  most  part  it  is  closely 
attached  to  the  pars  nervosa  and  infundibular  stalk.  The  pars 
intermedia  usually  invades  the  pars  nervosa  to  a  slight 
extent.  We  have  seen  that  in  Man  and  the  higher  mammals 
the  invasions  are  superficial  in  normal  circumstances,  but  that 
in  some  of  the  lower  animals  the  pars  nervosa  is  divided  up  by 
columns  of  cells. 

It  is  frequently  to  be  observed  that  in  the  part  which  is  in 
relation  to  the  stalk  there  are  many  vesicles  which  may  contain 
granular  secretion.  This  is  usually  neutrophil,  but  in  conditions 
to  be  mentioned  later  it  may  be  eosinophil.  Sometimes  the 
secretion  appears  homogeneous  like  colloid,  and  in  these  circum- 
stances it  is  usually  basophil  in  its  staining  affinity.  Occasionally, 
secretion  is  found  in  the  cleft,  and  is  no  doubt  derived  from  the 
cells  of  the  pars  intermedia. 

It  has  been  shown  that  in  different  animals  there  are  different 
degrees  of  secretory  activity  in  the  pars  intermedia,  so  far  as 
we  can  judge  from  the  formation  of  obvious  secretion  ;  and 
that  in  Man  there  is  little  evidence  of  the  production  of  secre- 
tion other  than  the  colloid  so  frequently  found  above,  and  in, 
the  cleft. 

In  abnormal  conditions  experimentally  produced  in  animals 
a  certain  blurring  and  fusing  of  the  cells  of  the  pars  intermedia 
appears  to  be  coincidental  with  increased  secretion. 

The  relationship  of  the  pars  intermedia  to  the  production  of 
infundibulin  will  be  discussed  directly  in  connexion  with  the 
functions  of  the  pars  nervosa. 

Pars  nervosa. — -We  have  seen  that  this  portion  of  the 
pituitary  is  chiefly  composed  of  neuroglial  cells  and  fibres,  and 
that  there  are  occasionally  to  be  found  a  few  ependymal  cells 
included  at  the  neck  in  those  animals  in  which  the  pars  nervosa 
is  solid.  When  there  is  a  central  cavity,  such  as  is  seen  in  the 
cat,  this  is  lined  with  ependymal  cells  the  fibres  of  which  run 
longitudinally  upwards  (Herring1).  Further,  we  have  considered 
the  question  of  the  nerve-supply  of  the  pituitary,  and  have  noted 
that    most    investigators    have    failed    to    find   true    nerve-fibres, 

1  Herring,  P.  T.,  Quart.  Jowrn.  Exper.  Physiol.  1908,  i,  121. 


96  PHYSIOLOGY 

and   that  it   is    doubtful   whether    sympathetics    are    present   in 
this  part  of  the  pituitary. 

We  must  now  consider  the  histological  and  accessory  evidence 
at  our  disposal  concerning  the  secretion  formed  by  the  pars 
nervosa  itself,  or  by  the  pars  intermedia  in  conjunction  with 
the  pars  nervosa.  Later,  we  shall  study  the  physiological  prop- 
erties of  the  extract  made  from  these  parts  of  the  pituitary, 
which  together  form  the  posterior  lobe  and  are  so  closely 
conjoined  as  to  be  inseparable  on  rough  dissection.  Whether 
this  extract  is  the  same  as  the  normal  secretion  we  need 
not  discuss,  beyond  saying  that  it  is  usually  believed  to 
be   so. 

We  have  already  seen  that  vesicles  are  nearly  always  to  be 
found  in  the  pars  intermedia,  and  these  contain  a  substance 
said  by  Biedl  to  resemble  in  appearance  thyroid  colloid,  but  in 
my  experience  it  is  more  usual  to  find  in  animals  a  neutrophil 
granular  secretion.  It  is  most  probable  that  this  material 
represents  the  normal  secretion  of  the  pars  intermedia. 

Osborne  and  Swale  Vincent1  found  that  by  careful  dissection 
they  could  separate  the  central  portion  of  the  posterior  lobe  from 
the  epithelial  investment,  and  that  whereas  an  extract  of  the 
former  gave  the  typical  effects  of  infundibulin,  an  extract  made 
from  the  epithelial  portion  gave  much  less  definite  results. 
Further  Osborne  and  Vincent2  have  shown  that  extracts  of  other 
nervous  tissues  do  not  possess  the  same  physiological  activity 
as  an  extract  of  the  posterior  lobe. 

Herring3  has  recently  confirmed  the  results  obtained  by 
Osborne  and  Vincent  to  the  extent  of  finding  that  although 
both  extracts  stimulate  muscle -contractions,  the  one  made  from 
the  pars  nervosa  is  from  two  to  five  times  more  powerful  than 
the  extract  of  the  pars  intermedia.  Herring  also  found  that 
an  extract  of  pars  intermedia  in  strengths  of  0*5  per  cent,  and 
less  has  no  specific  action  on  the  blood-pressure  or  renal  excre- 
tion ;  whereas  an  extract  of  the  pars  nervosa  in  so  low  a 
strength  as  0*005  per  cent,  produces  the  characteristic  pressor 
and  diuretic  effects  (see  pp.  105  and  109). 

1  Osborne,  W.  A.,  and  S.  Vincent,  Brit.  Med.  Jounu,  1900,  i,  502. 

2  Osborne,  W.  A.,  and  S.  Vincent,  Joum.  Physiol,  1899-1900,  xxv,  9. 

3  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol..  1915,  viii,  245  and  267. 


HISTOLOGICAL   INVESTIGATIONS  97 

Miller,  Lewis  and  Matthews1,  on  the  other  hand,  maintain 
that  it  is  the  cells  of  the  pars  intermedia  which  produce  infund- 
ibulin,  and  that  the  pars  nervosa  is  inactive  in  this  respect. 
These  observers  also  found  that  it  was  impossible  to  obtain 
pressor  effects  from  an  extract  of  the  stalk,  and  they  conclude 
that  "  there  is,  therefore,  a  distinct  interruption  in  the  path 
of  secretion  of  the  pressor  substance  from  the  pars  nervosa  to 
the  ventricle  ".  This  is  opposed  to  Herring's  view  concerning 
the  passage  of  secretion  from  the  pars  nervosa  to  the  third 
ventricle. 

Evidence  as  to  the  different  actions  of  extracts  of  the  pars 
intermedia  and  pars  nervosa  must  be  carefully  received  ;  for, 
in  the  first  place,  it  is  practically  impossible  to  remove  all  the 
epithelial  elements  from  the  surface  of  the  pars  nervosa,  especially 
in  the  region  of  the  stalk,  and,  in  the  second,  islets  of  pars  inter- 
media cells  may  be  found  in  the  pars  nervosa.  A  glance  at  some 
of  the  illustrations  in  the  section  on  comparative  anatomy  (p.  40 
and  following)  will  make  these  difficulties  obvious. 

Miller,  Lewis  and  Matthews1  obtained  pressor  effects  from 
the  contents  of  a  cyst  in  the  pars  intermedia.  Herring2  was 
unable  to  obtain  any  definite  effect  from  the  contents  of  the 
cleft.  Hamburger3,  likewise,  found  that  the  contents  of  the 
cleft  were  devoid  of  any  pressor  action. 

Herring4  was  the  first  to  describe  what  he  called  '  hyaline  ' 
bodies  in  the  pars  nervosa.  He  considers  that  they  represent 
the  active  secretion  of  the  cells  of  the  pars  intermedia,  which  is 
passed  into  the  pars  nervosa.  Further,  he  believes  that  these 
bodies  stream  upwards  towards  the  neck,  or  infundibulum,  and 
that  finally  they  pass  into  the  third  ventricle,  and  so  into 
the  cerebrospinal  fluid.  Herring  also  found  that  they  are 
very  much  more  numerous  in  the  pars  nervosa  after  thyroid- 
ectomy. 

Cushing  and  Goetsch5  subsequently  investigated  the  question, 
and   on  the   main   points   they   agree   with   Herring.     But  these 

1  Miller,  J.  L.,  D.  D.  Lewis,  and  S.  A.  Matthews,  Amer.  Journ.  Physiol.  (Proc. 
Amir.  Physiol.  Soc),  1910-1911,  xxvii,  xvii. 

2  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1915,  viii,  245  and  267. 

3  Hamburger,  W.,  Amer.  Journ.  Physiol,  1904,  xi,  282. 

4  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 

5  Cushing,  H,  and  E.  Goetsch,  Amer.  Journ.  Physiol,  1910,  xxvii,  GO. 

7 


98  PHYSIOLOGY 

writers  also  came  to  the  conclusion  that  some  of  the  '  hyaline  ' 
bodies  represent  degenerated  wandering  cells,  and  that  other 
'  hyaline  '  bodies  consist  of  secretion  which  has  escaped  or  has 
been  forced  from  the  vesicles  of  the  pars  intermedia.  They  state 
that  whereas  the  secretion  in  the  pars  intermedia  is  basophil, 
these  '  hyaline  '  bodies  are  faintly  eosinophil.  They  also  assert 
that  they  found  the  colloid  from  the  vesicles  physiologically 
inactive  ;  but  they  do  not  state  how  they  obtained  their  material. 
Last,  these  investigators  found  in  the  cerebrospinal  fluid  an 
active  substance  resembling  infundibulin  in  its  physiological 
actions.  From  this  they  conclude  that  it  is  proved  beyond 
doubt  that  the  active  principle  of  the  posterior  lobe  or  pars 
intermedia  is  passed  directly  into  the  third  ventricle. 

Now,  if  this  method  of  secretion  prove  to  be  indisputable, 
it  represents  a  most  remarkable  train  of  events,  and  one  which 
has  no  parallel  in  the  animal  economy.  But,  although  I  have 
myself  observed  all  the  histological  details  mentioned  by  these 
authors,  I  would  hesitate  to  conclude  that  to  histological 
features  so  unusual  in  connexion  with  secretory  activity  is  to  be 
assigned  the  representation  of  a  novel  method  for  the  distribution 
of  an  internal  secretion.  The  very  fact  that  some  so-called 
'  hyaline '  bodies  are  without  nuclei  and  others  contain  them 
indicates  the  true  nature  of  these  bodies  (fig.  69).  They  are  cells 
undergoing  degeneration,  which  may  in  the  process  disperse  their 
contents.  Again,  it  must  be  noted  that  they  are  always  very 
granular,  and  are  not  hyaline  in  structure  nor  do  they  re- 
semble the  homogeneous  colloid  seen  in  the  vesicles  of  the  pars 
intermedia  in  the  sightest  degree  ;  but  they  do  resemble  exactly 
the  granular  secretion-cells  and  masses  (fig.  53)  and  the  granular 
collections  in  the  vesicles  (figs.  49  and  52)  seen  in  the  pars  inter- 
media of  cats  and  dogs. 

On  histological  evidence  I  originally  formed  the  opinion  that 
the  cells  of  the  pars  intermedia  alone  produced  the  pressor  sub- 
stance which  I  called  'infundibulin'1. 

The  work  of  Miller,  Lewis  and  Matthews2  is  directly  opposed 
to  the  view  of  Herring,  for  they  found  that  an  extract  of  the 
stalk  had  no  pressor  action.     They  believe  that  the  cells  of  the 

1  Bel],  W.  Blair,  BriL  Med.  Journ,,  1909,  ii,  1609. 

2  Miller,  J.  L.,  D.  D.  Lewis,  and  S.  A.  Matthews,  Amer.  Journ.,  Physiol.  (Proc 
Amer.  Physiol.  Soc),  1910-1911,  xxvii,  xvii. 


HISTOLOGICAL   INVESTIGATIONS 


99 


pars  intermedia  alone  are  concerned  in  the  production  of  infund- 
ibulin. 

This  whole  question  is  undoubtedly  a  difficult  one,  but  I  feel 
that  the  idea  of  a  secretion  actively  moving  towards  the  third 
ventricle  is  disproved  by  the  fact  that  these  '  bodies  '  must  be 
degenerated  cells,  since  they  sometimes  possess  the  remains  of 
nuclei.  Yet  this  point  appears  to  have  been  noted  by  Herring, 
for  he  says :  "  Secretion  goes  on  either  by  emptying  of  material 
from  the   cells  into  the  lymph,  or  possibly  by  a  breaking  down 


Fig.  69. 

Section  of  the  pars  nervosa  of  the  normal  cat,  showing  granular  bodies,  some 
with  nuclei,  some  without.     (Photomicrograph.) 

X500. 

and  destruction  of  the  whole  cell.  The  latter,  indeed,  is  the 
more  probable  fate  of  isolated  epithelial  cells,  and  seems  to  occur 
at  times  in  the  epithelial  investment  itself"1. 

It  is,  moreover,  a  fact  of  some  importance  that  one  rarely 
sees  many  of  these  granular  bodies  in  normal  circumstances ; 
and  after  thyroidectomy  I  have  not  always  seen  a  great  increase 
in  their  number. 

My  present  opinion  is  that  the  secretion  of  the  pars  intermedia 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 


100  PHYSIOLOGY 

and  of  the  posterior  lobe  is  taken  up  by  the  blood-stream.  In 
support  of  this  view  attention  may  be  called  to  the  morpho- 
logical facts  that  there  is  a  network  of  blood-vessels  beneath 
the  pars  intermedia,  and  that  in  some  animals,  such  as  the  ox, 
the  pars  nervosa  has  a  very  rich  internal  blood-supply.  At  the 
.same  time  I  am  quite  aware  that  the  cells  of  the  pars  intermedia 
wander  into  the  pars  nervosa,  and  there  degenerate  (fig.  69). 
Any  secretion  they  contain  is,  no  doubt,  absorbed  by  the  capillary 
vessels.  It  seems  quite  possible,  also,  that  the  cells  of  the  pars 
intermedia  both  store  their  secretion  in  the  form  of  colloid  and, 
like  the  anterior  lobe,  pass  some  of  it  directly  into  the  blood- 
stream. In  order  to  reach  the  blood-vessels  the  secretion  may 
pass  through  the  pars  nervosa.  If  this  be  so,  as  seems  certain, 
it  is  possible  the  pars  nervosa  in  some  way  alters  the  character 
of  the  secretion  before  it  reaches  its  destination;  this  view1, 
which'  I  believe  to  be  correct,  whatever  the  final  destination 
of  the  secretion  may  be,   is  supported  by  Herring2. 

We  shall,  directly,  consider  more  fully  the  evidence  con- 
cerning the  question  of  the  presence  of  infundibulin  in  the 
cerebrospinal  fluid. 

1  Bell,  W.  Blair,  Arris  and  Gale  Lectures,  Lancet,  1913,  i,  937. 

2  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1914,  viii,  245. 


CHEMICAL  EXAMINATION  OF  THE  PITUITARY 
TISSUES,  AND  THE  EVIDENCE  REGARDING 
THE  PRESENCE  OF  INFUNDIBULIN  IN  THE 
BODY-FLUIDS 

CHEMISTRY    OF    THE    PITUITARY 

Very  little  work  has  been  carried  out  in  regard  to  the  chemistry 
of  the  pituitary  body. 

An  examination  of  the  whole  gland  shows  that  it  is  rich  in 
calcium  and  phosphorus,  but  this  may  be  on  account  of  the 
nervous  elements  in  the  pars  nervosa. 

Schnitzler  and  Ewald1  have  described  the  existence  of  iodine 
in  the  anterior  lobe,  and  concluded  that  it  is  probably  in  the  same 
form  as  in  the  thyroid  gland. 

Halliburton,  Candler  and  Sikes2,  and  Wells3  have  failed  to 
confirm  this  observation. 

Biedl4  states  that  the  colloid  in  the  anterior  lobe  is  in- 
soluble in  water,  alcohol  and  ether.  This  substance  is  unlike 
mucin  in  that  it  swells  with  acetic  acid,  and  afterwards  dissolves. 

The  secretion  of  the  posterior  lobe  is  soluble  in  water,  and  is 
not  destroyed  by  boiling;  consequently  the  active  principle  is 
not  a  protein.  It  has  been  found  to  be  dialyzable,  and  it  has 
certain  important  physiological  actions  that  will  be  described 
later. 

Suprarcnin,  which  is  probably  of  a  quite  different  chemical 
composition,  has  been  made  synthetically,  but  up  to  the 
present  time   the   actual    chemical   composition    of    infundibulin 

1  Schnitzler,  J.,  and  K.  Ewald,  Wien.  Klin.  Woch.,  1896,  ix,  657. 

2  Halliburton,  \V.  D.,  J.  P.  Candler,  and  A.   \V.   Sikes,  Quart.   Journ.   Exper 
Physiol,  1909,  ii,  229. 

3  Wells,  H.  G.,  Journ.  Biol.  Ghem.,  1909  1910,  vii,  259. 

4  Biedl,  A,  Innere  Sekretion,  2nd  ed.  1913. 


102  PHYSIOLOGY 

has  not  been  definitely  determined,  although  Aldrich1  has 
obtained  a  crystalline  pier  ate  and  sulphate  which  have  a  pressor 
action.  Houssay2,  also,  claims  to  have  obtained  infundibulin 
in  a  crystalline  form.  Recently  Fuhner3  has  placed  on  the 
market  a  substance  called  '  hypophysin  '.  This  is  stated  to 
contain  several  different  substances,  one  of  which  acts  on  the 
uterus  alone.  It  is  said  that  Fuhner 's  preparation  can  be  made 
from  both  the  anterior  and  posterior  lobes. 

Dale4  has  produced  evidence  to  show  that  infundibulin  is 
not  one  of  the  groups  of  bodies  to  which  belong  suprarenin, 
the  active  principles  of  ergot  and  the  pressor  substance  that  is 
found  in  putrid  meat. 

The  same  investigator  has  also  shown  that  whereas  ergotin 
annuls  the  effect  of  suprarenin  subsequently  given,  yet  it  in  no 
way  affects  the  action  of  infundibulin  on  arterial  and  uterine 
contractions. 

Schafer  and  Herring5  believe,  from  their  experiments,  that 
pepsin  destroys  the  pressor  effect  of  infundibulin,  but  docs  not 
interfere  with  its  diuretic  action.  They  state,  also,  that  trypsin 
has  no  effect  whatever  on  the  extract.  Dale4,  however,  ob- 
served exactly  reverse  effects  in  regard  to  the  actions  of  pepsin 
and  trypsin  ;  and  he  gives  some  very  convincing  tracings  of  his 
results.  Pepsin,  he  states,  does  not  change  infundibulin  at  all, 
whereas  trypsin  entirely  destroys  it  in  a  few  hours,  so  far  as  its 
physiological  activity  is  concerned. 


INFUNDIBULIN    AND    THE    CEREBROSPINAL    FLUID 

dishing  and  Goetsch6,  following  the  suggestion  of  Herring7 
concerning  the  passage  into  the  cerebrospinal  fluid  of  the  so- 
called  '  hyaline  '  bodies  which  may  be  seen  in  the  pars  nervosa, 

1  Aldrich,  T.  B  ,  Amer.  Journ.  Physiol.  (Proc.  Amer.  Physiol.  Soc),  1908, 
xxi,  xxiii. 

2  Houssay,  B.  A.,  Revist.  Soc.  Med.  Argent.,  Buenos  Aires,  1911,  268  (Reprint). 

3  Fiihner,  H.,  Zeitschr.  f.  d.  Ges.  Exper.  Med.,  1913,  i,  397. 

4  Dale,  H.  H.,  Biochem.  Journ.,  1909,  iv,  427. 

5  Schafer,  E.  A.,  and  P.  T.  Herring,  Proc.  Boy.  Soc.  Biol,  1906,  lxxvii,  Ser. 
B,  571. 

6  Gushing,  H.,  and  E.  Goetsch,  Amer.  Journ.  Physiol.,  1910,  xxvii,  60. 
'  Herring,  P.  T.,  Quart,  Journ.  Exper.  Physiol,  1908,  i,  121. 


INFUNDIBULIN  AND  THE  CEREBROSPINAL  FLUID    103 

endeavoured  to  prove  that  the  cerebrospinal  effusion  contains 
infundibulin.  Further.  Weed  and  dishing1  state  that  injections 
of  infundibulin  increase  the  rate  of  cerebrospinal  secretion. 
They  inserted  a  graduated  and  calibrated  needle  into  the 
third  ventricle  of  the  dog,  with  the  skull  and  meninges  intact 
except  for  a  small  perforation  equal  in  size  to  the  diameter  of 
the  needle.  The  drops  of  cerebrospinal  fluid  were  taken  as  an 
indication  of  the  secretory  rate.  These  investigators,  believing 
the  formation  of  cerebrospinal  fluid  to  be  secretory,  make  the 
surprising  statement  that  in  response  to  an  injection  of  infund- 
ibulin "  a  prolonged  flow  from  the  ventricle  may  continue  even 
after  death,  and  may  reach  an  amount  apparently  in  excess  of 
the  normal  content  of  the  ventricles  ".  This  seems  an  extra- 
ordinary post-mortem  phenomenon,  and  one  which  requires 
extensive  confirmation  before  it  can  be  seriously  considered. 

Carlson  and  Martin2  criticize  the  hypothesis  of  Herring  and 
the  observations  of  Cushing  and  Goetsch  regarding  the  passage 
of  infundibulin  directly  into  the  cerebrospinal  fluid.  These 
authors  say  :  "It  is  obvious  that  the  conclusions  drawn  by 
Cushing  and  Goetsch  from  their  experiments  are  open  to  a 
number  of  grave  objections.  The  cerebrospinal  fluid  used  in 
most  of  the  experiments  was  pathological,  and  was  concentrated 
20  to  25  times,  and  the  intravenous  injections  were  made  into 
another  species.  Finally,  no  control  experiments  were  reported 
on  blood  or  serum  from  the  same  individuals  yielding  the  cerebro- 
spinal fluid  ". 

Carlson  and  Martin  found  that  the  haemodynaniic  action  of 
the  cerebrospinal  fluid  was  solely  due  to  the  quantity  injected, 
as  is  the  case  with  defibrinated  blood  or  Ringer's  solution  :  there 
is,  in  fact,  no  evidence  of  a  specific  pressor  or  depressor  effect. 

These  observers  are  careful  to  state,  however,  that  their 
negative  results  do  not  prove  that  cerebrospinal  fluid  is  free 
from  pituitary  secretion  ;  but,  as  they  say,  we  have  as  yet  no 
satisfactory  test  for  this  secret  ion  in  the  fluids  of  the  body.  When 
such  tests  have  been  worked  out  Carlson  and  Martin  think  that 
the  distribution  of  pituitarj  secretion  in  the  body-fluids  will  prove 
to  be  similar  to  that  of  all  the  other  internal  secretions  so  far 

1  Weed,  L.  H.,  and  H.  Cushing,  Amer.  Journ,  Physiol.,  1915,  xxxvi,  77. 

2  Carlson,  A.  J.,  and  L.  M.  Martin,  Amer.  Journ.  Physiol,  1911,  xxix,  64. 


104  PHYSIOLOGY 

studied,  the  concentration  being  greatest  in  the  blood  and  least 
in  the  cerebrospinal  fluid.  With  these  statements  I  entirely 
agree. 

Cow1,  apparently  under  the  impression  that  the  cerebro- 
spinal fluid  has  definitely  been  proved  to  contain  infundibulin, 
asserts  that  the  infundibulin  content  of  this  secretion  is 
increased  after  injections  of  extracts  of  the  duodenal  mucous 
membrane,  which  he  believes  contains  a  hormone  that  excites 
activity  in  the  pituitary. 

1  Cow,  D.,  Journ.  Physiol.,  1915,  xlix,  441. 


INJECTION,    INGESTION    AND    ABSORPTION 
EXPERIMENTS 


IMMEDIATE     RESULTS     OF    INTRAVENOUS    INJECTIONS,    OF    ABSORP- 
TION   OF   EXTRACTS    IN    SOLUTION    AND    OF    GRAFTS 

Probably  the  most  important  and  fruitful  work  carried  out 
in  connexion  with  the  pituitary  has  been  concerned  with  the 
physiological  results  of  injections  of  the  extracts  into  the  living 
animal :  certainly  these  results  have  been  the  most  far-reaching 
in  their  application  to  morbid  conditions. 

In  this  place  I  shall  describe  the  physiological  actions  of  the 
extracts  on  the  different  organs  and  systems  as  obtained  in  the 
laboratory,  and  shall  merely  indicate  the  practical  application  of 
them,  for  this  aspect  of  the  subject  will  be  discussed  in  more 
detail  later. 

Circulatory  system 

In  1895  Oliver  and  Schafer1  described  the  action  of  an 
extract  of  the  whole  pituitary  upon  the  blood-pressure.  These 
observers  were,  at  the  time,  investigating  the  physiological  effects 
of  extracts  made  from  chief  organs  of  internal  secretion,  and 
they  also  gave  an  account  of  the  pressor  effect  of  suprarenal 
extract — that  is,  of  the  medullary  portion  of  this  organ. 
They  stated,  however,  that  the  suprarenal  extract  is  more 
powerful  in  this  respect  than  that  made  from  the  pituitary. 
As  the  result  of  these  observations  and  statements,  the 
suprarenal  product  obtained  clinical  recognition,  while  the 
physiologically  active  principle  of  the  pituitary  remained  in 
obscurity. 

1  Oliver,  (;.,  and  E.  A.  Schafer,  Journ.  Physiol.,  1895,  xviii,  277. 


106  PHYSIOLOGY 

In  1898  Howell1  made  some  further  observations. 

First,  he  found  it  is  the  extract  of  the  posterior  lobe  alone— 
that  is.  of  the  pars  nervosa  and  the  pars  intermedia,  which  come 
away  together  when  the  pituitary  body  is  divided  at  the  cleft — 
that  has  the  pressor  action.  In  this  respect  he  found  the  extract 
of  the  anterior  lobe  to  be  inactive — an  observation  subsequently 
confirmed  by  many  other  investigators. 

Second,  he  observed  that  the  cardiac  rhythm  is  consider- 
ably retarded,  and  that  the  heart-beat  is  increased  in  force  by 
the  injection  of  an  extract  of  this  portion  of  the  pituitary  (fig. 
70).  This  effect  is  believed  by  Dale2  to  be  partly  due  to  a  direct 
action  on  the  heart-muscle,  and  partly  to  a  retardation  of  the 
flow  in  the  coronary  vessels. 

Third,  Howell  noticed  that  second  and  subsequent  injections 
of  infundibulin,  if  given  soon  after  the  first,  produce  little  or  no 
effect  until  the  first  has  all  been  destroyed  or  excreted  by  the 
organism. 

In  the  following  year  Hedbom3  found  that  the  rate  of  beating 
in  the  isolated  mammalian  heart  is  considerably  decreased  on 
perfusion  with  infundibulin  in  Ringer's  solution.  Cleghorn4  in 
the  same  year  obtained  results  similar  to  those  described  by 
Hedbom. 

Also  in  1899,  Schafer  and  Swale  Vincent5  verified  these  experi- 
ments on  the  heart,  and  showed,  further,  that  the  slowing  of  the 
pulse  is  not  constant — an  observation  I  have  myself  confirmed 
in  regard  to  the  human  subject — but  that  when  present  the 
effect  is  not  abolished  by  atropine  or  by  section  of  the  vagi. 
These  observations  prove,  therefore,  that  the  action  of  the  extract 
is  peripheral  in  its  effect. 

Schafer  and  Vincent  noticed,  too,  that  a  fall  in  the  blood- 
pressure  follows  the  second  and  subsequent  doses,  if  they  be 
given  soon  after  the  first.  Osborne  and  Vincent6  subsequently 
found  that  this  effect  is  produced  by  the  depressor  substance 
found  in  most  organic  extracts.     It  is  certain,  moreover,  that  it 

1  Howell,  W.  H.,  Journ.  Exper.  Med.,  1898,  iii,  245. 

2  Dale,  H.  H.,  Biochem.  Journ,,  1909,  iv,  427. 

3  Hedbom,  K.,  Skand.  Arch.  /.  Physiol,  1899,  \iii,  147. 

4  Cleghorn,  A.,  Amer.  Journ.  Physiol,,  1899,  ii,  273. 

5  Schafer,  E.  A.,  and  S.  "Vincent,  Journ,  Physiol,,  1899,  xxv,  87. 

6  Osborne,  W.  A.,  and  S.  Vincent,  Brit.  Med.  Journ.,  1900,  i,  502. 


INJECTION   EXPERIMENTS 


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108  PHYSIOLOGY 

is  usual  to  see  a  preliminary  fall  of  blood-pressure  before  the 
rise  occurs  (fig.  70). 

Mummery  and  Symes1,  and  Hick  and  I2  independently 
observed  that  the  blood-pressure  is  maintained  at  a  high  level 
for  a  much  longer  period  of  time  than  is  seen  after  an  injection 
of  suprarenin.  We  also  observed,  as  others  had  done,  that  a 
second  dose  has  little  or  no  effect  until  some  time  has  elapsed 
since  the  administration  of  the  first  dose. 

We  shall  sec  directly  that  it  has  been  stated  that  infund- 
ibulin  has  a  specific  effect  in  regard  to  the  renal  vessels, 
but  this  point  is  best  discussed  in  regard  to  the  production 
of  diuresis. 

Dale3  and  de  Bonis  and  Susanna4  have  shown  that  con- 
traction is  produced  in  the  pulmonary  arteries  and  arterioles  by 
infundibulin.  This  is  interesting  in  view  of  the  facts,  demon- 
strated by  Brodic  and  Dixon5,  that  the  muscular  coats  of  the 
smaller  arteries  of  the  lung  are  not  under  the  control  of  the  sym- 
pathetic nervous  system,  and  that  suprarenin  does  not  produce 
vaso-constriction  in  them.  The  coronary  arteries,  also,  are 
thought  by  some67  to  be  independent  of  sympathetic  control  ; 
but,  like  the  pulmonary  arteries,  they  are  affected  by  the  pressor 
action  of  infundibulin3,4'8. 


Spleen 

Magnus  and  Schafer9  have  shown  that  infundibulin  causes 
contractions  in  the  muscular  coat  of  the  spleen,  producing  a 
decrease  in  the  volume  of  the  organ.  Dale3  has  confirmed 
this  observation. 

We  shall  see  that  advantage  may  be  taken  of  this  effect  in 
certain  affections  of  the  spleen. 

1  Mummery,  P.  L.,  and  L.  Symes,  Brit.  Med,  Journ.,  1908,  ii,  786. 

2  Bell,  W.  Blair,  and  P.  Hick,  Brit.  Med,  Journ.,  1909,  i,  777. 

3  Dale,  H.  H.,  Biochem.  Journ.,  1909,  iv,  427. 

4  Bonis,  de  V.,  and  W.  Susanna,  Zentralbl.  fur  Physiol,  1909,  xxiii,  169. 

5  Brodie,  T.  G.,  and  W.  E.  Dixon,  Journ.  Physiol,  1904,  xxx,  479. 

6  Schafer,  (quoted  by  Dale3)  Arch,  de  Sci.  Biol,  de  St.  Petersburg,  1904,  251. 

7  Elliott,  T.  R,  Journ.  Physiol,  1905,  xxxii,  401. 

8  Pal,  J.,  Zentralbl.  fur  Physiol,  1909,  xxiii,  253. 

9  Magnus,  R,  and  E.  A.  Schafer,  Journ.  Physiol,  1901-1902,  xxvii,  9. 


INJECTION   EXPERIMENTS  109 

Respiratory  system 

Mummery  and  Symes1  observed  that  a  diminution  in  the 
amplitude  of  the  respiratory  movements  is  produced  by  an 
injection  of  infundibulin — an  effect  that  may  have  some  con- 
nexion with  the  action  of  infundibulin  on  the  pulmonary  circul- 
ation, already  described.     This  is  a  matter  of  clinical  importance. 

Urinary  system 

Kidneys. — -In  1901  Magnus  and  Schafer2  published  experi- 
ments to  show  that  the  extract  of  the  posterior  lobe  produces 
diuresis.  Further,  they  stated  that  whereas  all  the  other 
arteries  in  the  body  are  constricted  by  the  active  principle  of  the 
extract,  the  arteries  of  the  kidney  are  dilated,  and  that  there 
is  an  increase  in  the  kidney-volume.  Subsequently,  Schafer  and 
Herring3  found  that  diuresis  occurred  even  when  the  arteries 
in  the  kidney  failed  to  dilate,  and  when  the  general  vasocon- 
striction was  absent  after  repeated  doses  of  the  extract  ;  con- 
sequently they  came  to  the  conclusion  that  there  must  be  direct 
stimulation  of  the  secretory  cells  of  the  kidney  during  the  excre- 
tion of  a  specific  active  principle. 

Herring4  has  recently  stated  that  it  is  only  an  extract  from 
the  pars  nervosa  that  produces  diuresis  and  an  increase  in  the 
kidney-volume.  An  extract  made  from  the  pars  intermedia, 
like  that  of  the  pars  anterior,  is  inactive  in  this  respect. 

The  view  of  Schafer  and  Herring  that  there  is  stimulation 
of  the  secretory  cells  of  the  kidney  by  the  extract  of  the  pars 
nervosa  has  found  support  in  the  experiments  of  Dale5,  who  has 
observed  that  infundibulin  is  excreted  in  the  urine.  Further,  Dale 
does  not  believe  that  there  are  two  active  principles,  but,  rather, 
that  there  is  one  which  has  both  a  pressor  and  a  diuretic  effect. 

Gushing0  believes  that  the  pars  posterior  contains  both 
glycogenolytic  and  diuretic  substances. 

1  Mummery,  P.  L.,  and  L.  Symes,  Brit,  Med.  Joum.,  1908,  ii,  786. 

2  Magnus,  R.,  and  E.  A.  Schafer,  Joum.  Physiol.,  1901-1902,  xxvii,  9. 

3  Schafer,  E.  A.,  and  P.  T.  Herring,  Proc.  Roy.  Soc.  Biol.,  1906,  lxxvii,  Ser. 
B,  571. 

4  Herring,  P.  T.,  Quart.  Joum.  Exper.  Physiol.,  1915,  \  iii,  215  and  267. 

5  Dale,  H.  H.,  Bio-chem.  Jowrn.,  1909,  iv,  427. 

6  Gushing,  H.,  Boston  Med.  and  Surg.  Joum.,  1913,  clxvhi,  901. 


110  PHYSIOLOGY 

Cow1  has  recently  endeavoured  to  prove  that  the  pituitary 
is  activated  in  regard  to  its  diuretic  function  by  a  hormone  from 
the  gastrointestinal  tract  which  is  absorbed  along  with  ingested 
fluids.  Hashimoto2  had  previously  stated  that  the  diuretic  effect 
of  extracts  of  the  duodenal  mucous  membrane  is  entirely  due  to 
their  saline  contents.  Cow,  however,  disputes  this  point  of  view, 
and  adduces  arguments  in  favour  of  the  specificity  of  duodenal 
extract  in  the  respect  mentioned. 

Bladder. — Frankl-Hochwart  and  Frohlich3  first  described  the 
effect  of  infundibulin  on  the  bladder.  They  state  that  strong 
contractions  are  always  produced. 

Dale  and  Laidlaw4  were  unable  to  obtain  the  same  result, 
and  in  our  earlier  experiments5  we  did  not  observe  any  definite 
action  on  the  vesical  musculature.  Subsequently,  I  found  that 
in  the  presence  of  considerable  distension — such  as  could 
be  produced  by  the  use  of  the  cannula  and  manometer 
apparatus,  to  be  described  presently  in  connexion  with  the 
recording  of  uterine  contractions — expulsive  contractions  can 
usually  be  produced  by  the  intravenous  administration  of 
infundibulin  (fig.  71). 

I  found,  too,  that,  after  the  bladder  had  apparently  been 
emptied  with  a  catheter  and  only  an  occasional  drop  of  urine  was 
following,  an  intravenous  injection  of  infundibulin  caused  the 
immediate  evacuation  of  the  residual  urine  in  a  series  of  rapid 
drops,  and  that  shortly  after  the  bladder  had  been  completely 
emptied  a  further  rapid  outflow  of  drops  occurred  (fig.  72).  The 
second  flow  probably  represented  increased  secretion  from  the 
kidneys — that  is,  a  diuretic  effect. 

Wc  shall  see  later  that  in  clinical  practice  infundibulin  is 
very  unreliable  in  regard  to  the  evacuation  of  the  bladder. 

1  Cow,  D.,  Journ.  Physiol.,  1915,  xlix,  441. 

2  Hashimoto,  M.,  Arch.  f.  Exper.  Pathol,  u.  Pharkamol,  1914.  Ixxvi,  367. 

3  Frankl-Hochwart,  L.  von,  and  A.   Frohlich,  Arch.  /.  Exper.  Pathol,   tt.  Phar- 
makol,  1910,  lxiii,  347. 

4  Dale,  H.  H.,  and  P.  P.  Laidlaw,  Journ,  Pharmacol,  and  Exper.  Therap.,  1912, 
iv,  75. 

5  Bell,  W.  Blair,  and  P.  Hick,  Brit.  Med.  Journ.,  1909,  i,  777. 


Kymograph -tracing  shfhere  is  an  immediate  expulsion  of  residual  urine,  and 

[To  face  page  110. 


Kyi!Mi:r:L|>h-tr;u-iiiL'  ^ho\\  »ia  euntn-irtiuns  nt  l  In-  i.li>tviuli-il  Madder  of  the  cat  after  an  inject iuii  <A  in:  innlil.nl in. 


Kuno^iaj.li-tidi-'ing  -\n>\\  mil:  tin   c-tk-t-l  nf  infimdibnlin  c 


nediate  expulsion  of  residual  urine,  and 
[Tofacfpage  110. 


INJECTION   EXPERIMENTS  111 


Uterus 


In  1907  we  were  engaged  in  investigating  uterine  contrac- 
tions in  the  rabbit1.  Extracts  of  all  the  ductless  glands  were 
employed,  and  among  them  an  extract  of  the  posterior  lobe 
of  the  pituitary  obtained  from  the  ox. 

We  found  that  although  the  resting — that  is,  the  non- 
pregnant and  non-cestrous — uterus  in  the  rabbit  did  not  react, 
the  menstruating  and  pregnant  uterus  contracted  very  violently 
in  pithed  animals,  when  an  intravenous  injection  was  given. 
We  noticed,  also,  that  the  range  of  action  was  considerably 
longer  and  more  powerful  than  was  the  case  when  suprarenin 
had  been  injected. 

Before  this  date  Dale2  had  illustrated  incidentally  the  effect 
of  an  extract  of  the  pars  posterior  upon  the  uterus,  but  the  illus- 
tration with  no  comment  in  the  text  was  buried  in  a  paper  on  the 
action  of  ergot,  and  was  quite  unknown.  It  is  possible  that  other 
laboratory  workers  may  have  used  infundibulin  for  comparative 
tests. 

In  a  later  paper  Dale3  criticized  the  negative  results  obtained 
on  the  resting  uterus  of  the  rabbit,  and  he  stated  that  the  resting 
uterus  of  the  cat  will  always  react  to  the  extract.  It  must  be 
remembered,  however,  that  the  resting  uterus  of  the  rabbit 
undergoes  marked  seasonal  changes,  in  the  winter  especially, 
when  there  is  a  considerable  degree  of  atrophy. 

Dale  made  the  valuable  observation  that  whereas  the  effect  of 
suprarenin  on  the  uterus  is  negatived  by  a  previous  injection 
of  ergotine,  the  action  of  infundibulin  is  not  affected  in  the  same 
way. 

In  estimating  the  degree  of  contraction  we  employed  a  new 
method  whereby  a  special  cannula  (fig.  73)  full  of  saline  solution 
was  passed  up  the  vagina,  and,  under  guidance  through  a  small 
incision  in  the  abdominal  wall,  into  a  uterine  horn  in  which  it 
was  tied  with  a  woollen  ligature.  The  cannula  was  then  con- 
nected with  a  manometer  containing  saline  solution  and  attached 
to  an  air-bellows  with  a  recorder.     By  this  means  we  obtained 

1  Bell,  W.  Blair,  and  P.  Hick,  Brit.  Med,  Journ,,  1909,  i,  777. 

2  Dale.  H.  H.,  Journ.  Physiol,  1900,  xxxiv,  163. 

3  Dale.  H.  H..  Biochem.  Journ.,  1909,  iv,  427. 


112 


PHYSIOLOGY 


a  record  of  the  total  expulsive  effect.  Figure  70  shows  a  tracing 
of  the  effect  produced  on  the  uterine  contractions,  as  well  as  on 
the  blood-pressure,  by  an  intravenous  injection  of  infundibulin 
in  a  pregnant  cat. 

Further,  we  found  that  the  isolated  uterus  suspended  in 
Ringer's  solution  contracts  on  the  addition  of  infundibulin — an 
effect  that  indicates  that  the  action  of  infundibulin  on  the  uterus 
is  peripheral. 


Fig.  73. 
Uterine  cannula  for  recording  the  expulsive  contractions  of  the  uterus  in  animals. 


Alimentary  tract 

Intestines. — During  the  course  of  our  work  on  uterine  con- 
tractions we  discovered  that  the  infundibular  extract  may 
produce   a   remarkable  pressor  effect  on  the  intestinal   muscles. 

Our  attention  was  first  called  to  this  phenomenon  by  the 
observation  that  on  several  occasions  actual  defecation  was 
produced  at  regular  intervals  in  a  pithed  rabbit.  At  each 
evacuation  there  was  a  sudden  rise  in  the  blood-pressure  (fig.  74). 

Records  of  the  intestinal  movements  are,  however,  best 
obtained  by  tension-sutures  attached  to  a  piece  of  isolated  bowel 
suspended  in  Ringer's  solution,  and  connected  with  a  lever. 
In    many  cases  we   find   that   on   the   addition    of   infundibulin 


INJECTION   EXPERIMENTS 


113 


to  the  solution  there  is  relaxation,  and  cessation  of  the  normal 
contractions  (fig.  75)  ;  but  that  often  this  is  preceded  by  a 
powerful  contraction  (fig.  76). 

Ott  and  Scott1,  Houssay2  and  others  have  confirmed  these 
results. 

Bayer  and  Peter3  found  that  in  the  isolated  intestine  after 
an  initial  diminution  in  the  movements  there  is  a  marked  increase 
in  their  amplitude.  These  observers  consider  the  first  effect 
to  be  due  to  stimulation  of  the  sympathetic  fibres  which  inhibit 
the  muscular  contractions,  and  that  the  second  is  the  result  of 
the  stimulation    of   the  nerve-fibres    connected   with  Auerbach's 


Fig.  74. 

Kymograph -tracing  showing  rises  in  the  elevated  blood-pressure  corresponding 
to  acts  of  defecation  (D)  in  the  rabbit  after  an  injection  of  infundibulin. 


plexus.     Bayer  and  Peter  think  that  there  are  two  active  prin- 
ciples responsible  for  these  opposite  effects. 

Young4,  also,  has  recently  shown  that  infundibulin  has  a  well- 
marked  action  on  the  intestine  of  the  cat,  raising  the  tone  and 
causing  the  development  of  large  oscillations  ;  but  he  points 
out  that  the  watery  solution  of  the  extract  must  be  fairly 
strong — not  less  than  2  per  cent. 

1  Ott,  I.,  and  J.  C.  Scott,  Proc.  Soc.  Exper.  Biol,  and  Med.,  1911,  viii,  48. 

2  Houssay,  B.  A.,  La  Ciencia  Med.,  Buenos  Aires  (Reprint.  Xo  date);  Revist. 
Soc.  Med.  Argent.,  Buenos  Aires,  1911,  268  (Reprint). 

3  Bayer,  G.,  and  L.  Peter,  Arch.  f.  Exper.  Pathol,  u.  Pharmakol.,  1911,  lxiv,  204. 

4  Young.  A.  W.,  Quart.  Journ.  Exper.  Physiol,  1915,  viii,  347. 

8 


114  PHYSIOLOGY 

Dale  and  Laidlaw1  working  with  dogs  were  unable  to  obtain 
any  increase  in  the  intestinal  movements. 

As  we  shall  see,  there  is  little  doubt  as  to  the  power  of  infund- 
ibulin  to  produce  contractions  in  the  atonic  intestinal  muscles 
of  the  human  subject — a  condition  occasionally  seen  after 
abdominal  operations. 

It  may  be  mentioned  here  that  we  have  found  that  com- 
paratively the  greatest  range  of  action  both  in  regard  to  the 
blood-pressure,  intestinal  movements,  and  uterine  contractions 
can  be  obtained  when  there  is  loss  of  tone  in  the  muscles 
concerned. 

Stomach. — In  1910  I  recommended  infundibulin  for  the 
treatment  of  postoperative  atony  and  dilation  of  the  stomach2. 
The  effect  obtained  clinically  was  subsequently  confirmed  experi- 
mentally by  Houssay3 — the  pressor  effect  being  observed  on  the 
isolated  stomach.  This  investigator4  has  also  noted  that  injec- 
tions of  infundibulin  cause  an  increase  in  the  flow  of  gastric 
juice,  due  to  stimulation  of  the  secreting  cells. 

Mammary  glands 

In  1911  Ott  and  Scott5  announced  that  infundibulin  acts 
as  a  galactogogue  on  the  actively  secreting  mammary  gland. 
MacKenzie6  subsequently  confirmed  this  finding.  This  is  an 
unexpected,  and  at  present  not  satisfactorily  explained,  phenom- 
enon. The  effect  is  so  rapid  that  it  would  seem  improbable 
that  the  active  principle  is  excreted  by  the  mammary  glands, 
and  in  its  passage  stimulates  the  secreting  cells. 

Hammond7  states  that  the  effect  is  not  brought  about  by 
the  expulsion  of  milk  which  is  stored  in  the  cells  and  would 
have  been  obtained  at  the  next  milking,  but  rather  by  stimu- 
lation of  the  mammary  epithelium.  Nevertheless,  Hammond 
found  only  a  slight  increase  of  the  daily  yield  of  milk.      Further, 

1  Dale,  H.  H.,  and  P.  P.  Laidlaw,  Journ.  Pharmacol,  and  Exper.  Therap.,  1912, 
iv,  75. 

2  Bell,  W.  Blair,  The  Principles  of  Qynoecology,  1910. 

3  Houssay,  B.  A.,  La  Ciencia  Med.,  Buenos  Aires  (Reprint.     No  date). 

4  Houssay,  B.  A.,  La  Sem.  Med.,  Buenos  Aires,  1913  (No.  46)  p.  5. 

5  Ott,  L,  and  J.  C.  Scott,  Proc.  Soc.  Exper.  Biol,  and  Med.,  1911,  viii,  48. 

6  MacKenzie,  K.,  Quart,  Journ.  Exper.  Physiol.,  1911,  iv,  305. 

7  Hammond,  J.,  Quart.  Journ.  Exper.  Physiol.,  1913,  vi,  311. 


Normal     bowtl     contractions 


relaxation  after  addition  of  Infundibul 


' of  'in/undibuiin  ioRi ngtr's  i olution  " 


Fig. 


ograph-tracing  showing  the  effect  of  infundibulin  on  the  cat's  isolated  small  intestine  suspended  in  I 
olution.     In  this  case  there  was  relaxation  (upward  release  of  the  lever)  without  previous  contractic 


]  Infundibulin  added  to  Ringer's  solution 


Fig.  76. 

Kymograph-tracing  showing  the  effect  of  infundibulin  on  the  cat's  isolated  small  intestine  suspent 
ger's  solution.  There  was  an  immediate  forcible  contraction  (downward  pull  on  the  lever)  follow 
xation. 

[To  face  pa 


INJECTION   EXPERIMENTS  115 

Hammond  states  that  the  quality  of  the  milk  procured  by  the 
injection  of  infundibulin  is  normal  except  for  an  increase  in  the 
percentage  of  fat.  It  was  found,  however,  that  in  the  subse- 
quent milkings  there  was  a  drop  in  the  fat-percentage,  the  other 
constituents  remaining  normal. 

There  is  no  evidence  that  the  increased  secretion  is  due  to 
elevation  of  the  blood-pressure,  for  it  is  said  by  Schafer  and 
MacKenzie1  and  by  Hammond2,  that  expulsion  of  milk  occurs, 
although  in  lessened  quantities,  after  repeated  doses  of  the  ex- 
tract, in  which  circumstances  the  blood-pressure  is  not  raised. 
Hammond,  and  Simpson  and  Hill3  state  that  there  is  a  rapid  de- 
crease in  the  quantity  of  milk  to  be  obtained  after  the  first  increase. 
.  I  have  found  that  if  one  gland,  from  which  the  nipple  has 
been  amputated,  be  exhausted  after  an  intravenous  injection 
(fig.  77),  and  the  nipple  from  another  mamma  on  the  same  animal 
be  amputated  fifteen  minutes  later,  there  will  also  be  an  im- 
mediate, rapid  outflow  of  milk  from  this  organ,  as  the  result  of 
the  intravenous  injection  of  infundibulin  administered  in  the 
first  instance  (fig.  78).  This  is  interesting  in  connexion  with 
the  fact4  that  an  histological  examination  of  adjacent  mammary 
glands,  one  of  which  has  been  incised  and  emptied  by  the  ad- 
ministration of  infundibulin,  shows  that  in  the  exhausted  gland 
the  alveoli  are  empty  and  their  walls  are  retracted,  while  in  the 
adjacent  mamma  the  alveoli  are  distended  with  milk  (fig.  79). 

Hammond's  and  MacKenzie's  experiments  appear  to  some 
extent  to  negative  the  view  that  infundibulin  acts  on  muscular 
tissue  in  the  breasts,  and  thus  leads  to  the  mechanical  expulsion 
of  milk.  Schafer4,  however,  in  a  recent  paper,  opposes  the  view 
that  the  infundibular  hormone  stimulates  the  secretory  epi- 
thelium of  the  mammae,  and  expresses  the  opinion  that  the 
increase  in  the  milk  obtained  is  due  to  contraction  of  plain  muscle- 
lil>res  in  the  alveoli.  It  appears  to  me  that  all  the  experimental 
facts  accord  best  with  this  view,  that  the  increase  in  the  rate  of 
expulsion  is  due  to  a  single  pressor  effect  upon  the  muscle-fibres 
in  the  walls  of  the  alveoli — a  view  held  by  most  physiologists. 

1  Schafer,  E.  A.,  and  K.  MacKenzie,  Proc.  Roy.  Soc.  Biol,  1911,  Lxxxiv,  Ser.  B. 
16. 

2  Hammond,  J.,  Quart.  Journ.  Exper.  Physiol.,  1913,  vi,  311. 

3  Simpson,  S.,  and  R.  L.  Hill-  Quart.  Journ.  Exper.  Physiol,  1915,  viii,  377. 
1  .Schafer,  E.  A.,  Quart.  Journ.  Exper.  Physiol,  1915,  viii,  379. 


116 


PHYSIOLOGY 


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INJECTION   EXPERIMENTS 


117 


Apart  from  the  effect  of  infundibulin,  just  mentioned,  on  the 
mammae  of  the  lactating  animal — due  partly  to  the  natural 
elasticity  of  the  walls  of  the  alveoli,  and  partly  to  the  con- 
traction of  the  unstriped  muscle  to  be  found  therein — the 
epithelial  cells  in  the  alveoli  may  be  emptied  of  their  milk 
contents  during  the  process.  I  have,  however,  been  able  to 
obtain  but  slight  evidence  that  the  secretion  in  the  cells  is  added 
to  that  in  the  alveoli  already  distended  and  unable  to  evacuate 
their  contents.  An  histological  examination  of  the  mammas  of 
a  lactating  animal  removed  before  and  after  the  administration 


Fig.  79. 

Section  of  the  edges  of  adjoining  mammae  in  the  guinea-pig,  showing  below 
alveoli  emptied  after  an  intravenous  injection  of  infundibulin  and  excision  of  the 
nipple,  and  above  the  alveoli  of  the  adjacent  unemptied  mamma. 

X  125. 

of    infundibulin   shows    a    slight    difference    in   the    size    of    the 
alveoli  in  the  different  circumstances   (fig.  80). 

I  have,  also,  made  experiments,  hitherto  unrecorded,  which 
bear  on  the  question  of  the  stimulation  of  mammary  secretion. 
Strictly  speaking,  they  concern  the  late,  rather  than  the  im- 
mediate, action  of  the  pituitary  hormones,  but  I  shall  consider 
them  here  rather  than  under  the  next  sub-heading. 


118 


PHYSIOLOCxY 


I  was  anxious  to  discover  whether  the  mammary  epithelium 
of  the  virgin  animal  could  be  stimulated  into  any  semblance  of 
secretory  activity  by  injections  of  pituitary  extracts.  In  all 
cases  one  mamma  was  first  removed  to  serve  as  a  control  to 
the  subsequent  histological  examinations  of  the  remaining 
mammary  glands  at  the  conclusion  of  the  experiments. 


Fig.  80. 

Sections  of  mamrnSe  from  a  guinea-pig.  On  the  left  are  shown  the  alveoli  of 
a  mamma  removed  for  control.  On  the  right  are  the  alveoli  of  the  corresponding 
mamma  of  the  opposite  side,  from  which  the  milk  was  not  allowed  to  escape  after 
an  intravenous  injection  of  infundibulin.  It  will  be  noticed  that  there  is  apparently 
a  slight  filling  of  the  vesicles  after  the  administration  of  infundibulin. 

X  125. 

1.  Three  adult  virgin  guinea-pigs  received  injections  of  a 
saline  extract  of  the  pars  anterior.  Of  these  two  received 
20  injections  of  0*5  c.c.  of  this  extract  (equivalent  to  0*25 
gramme  of  fresh  pars  anterior  substance)  on  alternate  days  ; 
and  one  only  7  injections,  when  it  died. 

2.  Six  adult  virgin  guinea-pigs  received  injections  of  a 
saline  extract  of  the  pars  posterior.  Of  these  three  received 
18  injections  of  0*1  c.c.  (equivalent  to  0*02  gramme  of  fresh 
pars  posterior  substance).  They  were  all  found  dead  on  the 
day  after   the    last  injection,   and   on  the   same  date.     The 


INJECTION    EXPERIMENTS  119 

other  three  animals   each  received   27  daily  injections,  and 
remained  well. 

The  mammae,  removed  from  the  animals  in  both  experi- 
ments, after  they  had  died  or  had  been  killed,  were  carefully 
examined,  but  in  no  case  was  any  change  observed  which  could 
be  construed  into  an  indication  of  secretory  activity. 

It  seems  probable,  therefore,  that  extracts  of  the  pituitary 
cannot  of  themselves  arouse  activity  in  the  breasts.  At  the  same 
time,  it  is  not  possible  to  assert  on  the  evidence  of  these  experi- 
ments, which  were  concerned  with  virgin  animals,  that  infund- 
ibulin  does  not  affect  the  secretion  of  mammae  already  lactating. 

It  may  be  stated,  then,  that  the  problem  of  the  cause  of  the 
immediate  increase  in  the  flow  of  milk  in  a  lactating  animal,  which 
is  very  definite,  is  still  not  completely  solved. 


Dilator  muscles  of  the  iris 

In  1908  Cramer1  showed  that  infundibulin  produces  dilatation 
of  the  pupil  in  the  enucleated  eye  of  the  frog.  On  the  other 
hand,  Dale2  states  that  no  such  effect  can  be  obtained  on  the 
mammalian  eye. 


Pancreatic  secretion 

There  is  one  more  interesting  study  of  the  effects  of  the 
injections  of  extracts  to  which  allusion  must  be  made.  I  refer 
to  the  action  of  infundibulin  on  the  secretion  of  the  pancreas. 

Pemberton  and  Sweet3  have  done  the  most  important — 
indeed,  the  only  important — work  on  this  subject.  These 
observers  found  that  the  pancreatic  secretion  is  inhibited  by 
injections  of  infundibulin.  This  result  is  produced  repeatedly, 
even  when  the  blood-pressure  fails  to  rise  after  subsequent 
injections.  Inhibition  is  also  caused  when  the  pancreas  is 
stimulated  by  the  normal  excitant — hydrochloric  acid — in  the 
duodenum. 

1  Cramer,  W.,  Quart.  Joiirn.  Exper.  Physiol.,  1908,  i,  189. 

2  Dale,  H.  H.,  Biochem.  Journ.,  1909,  iv,  427. 

3  Pemberton,  R.,  and  J.  E.  Sweet,  Arch.  Int.  Med.,  1910,  v,  466. 


120  PHYSIOLOGY 

Immediate  results  of  absorption  from  grafts 

This  has  long  been  a  recognized  method  of  proving  that 
certain  tissues  possess  an  internal  secretion,  and  grafts  of  most 
of  the  hormonopoietic  glands  have  been  successfully  implanted, 
and  have  continued  physiologically  active  for  a  time.  It  is,  of 
course,  a  method  of  local  absorption.  We  have  already  noted 
the  effect  of  infundibulin  in  Ringer's  solution  on  the  uterus  and 
other  involuntary  muscles — a  method  of  local  absorption  utilized 
to  test  the  mode  of  action  of  the  extract  on  these  muscles.  By 
the  method  of  grafting  we  may  obtain  the  normal  effects  of  the 
internal  secretion  of  the  organ  concerned. 

From  the  work  that  has  been  done  on  this  subject  we  know 
that  certain  conditions  and  circumstances  greatly  assist  or  modify 
the  results  of  this  procedure.  Thus,  it  is  almost  an  universal 
rule  that  autoplastic  transplantation — that  is,  the  removal  of  an 
organ  or  a  portion  of  it  from,  and  reimplantation  into,  the  same 
individual — is  far  more  successful  in  the  immediate  and  late 
results  than  homoplastic  grafting,  in  which  the  organ  of  one 
individual  is  transplanted  into  another  of  the  same  species,  or  of 
heteroplastic  substitution  from  another  species. 

Halsted1  laid  down  that  for  really  successful  transplantation 
there  must  be  considerable  insufficiency  of  the  internal  secretion 
in  question — in  other  words,  the  whole  or  a  large  portion  of  the 
particular  organ  must  be  removed  if  implantations  of  the  same 
structure  are  to  be  successful. 

I  have  tested  this  statement  in  regard  to  the  grafting  of 
ovaries — one  ovary  being  removed  and  after  suitable  treatment 
reimplanted,  and  the  other  left.  It  was  found  subsequently,  at 
various  periods,  that  the  grafts  were  in  an  active  condition  in 
spite  of  the  existence  of  one  normal  ovary.  My  investigations, 
therefore,  do  not  entirely  support  Halsted's  view.  It  is  a  most 
important  question,  for,  if  a  successful  reimplantation  can  be 
carried  out — as  I  believe — before  the  total  removal  of  an  organ  of 
internal  secretion,  a  patient's  life  may  in  this  way  be  secured 
from  serious  disturbances  or  from  jeopardy. 

Further,  it  is,  of  course,  essential  in  all  cases  of  grafting  that 
the  implantation  should  be  made  where  there  is  a  good  blood- 
supply.  I  have  never  favoured  the  peritoneal  cavity  or  equally 
1  Halsted,  W.  S.,  Jovrn.  Exper.  Med.,  1909,  xi,  175. 


ABSORPTION   FROM   GRAFTS  121 

avascular  sites,  because  in  such  situations  the  graft  is  often 
smothered  by  a  dejjosit  of  lymph,  and  perishes  before  vascular 
connexions  can  be  established.  Implantation  into  the  kidney 
has  been  practised  with  considerable  success  in  the  case  of  the 
ovary  ;  but  grafts  appear  to  do  equally  well  when  placed  in 
muscle,  a  situation  which,  at  any  rate  in  the  case  of  the  human 
subject,  is  the  safest  and  most  convenient. 

Moreover,  the  grafts  must  be  thin  :  it  is  useless  to  attempt  to 
implant  large  blocks  of  any  organ,  for  the  central  portions  under- 
go necrosis  before  the  blood-supply  can  be  established. 

Last,  it  is  hardly  necessary  to  add  that  perfect  asepsis  is 
essential  to  success. 

Very  few  observers  seem  to  have  studied  the  question  of 
the  implantation  of  the  pituitary  body.  Crowe,  Gushing  and 
Homans1,  as  we  shall  see  later,  were  able  to  prolong  the  life 
of  some  of  their  dogs  by  previous  or  simultaneous  implanta- 
tion of  the  anterior  lobe,  but  in  no  case  was  a  permanent  effect 
obtained. 

Schafer2  failed  to  secure  good  results.  He  employed  homo- 
plastic and  heteroplastic  grafts  in  animals  from  which  the 
pituitary  had  not  been  removed.  Both  of  these  circumstances 
may  have  militated  against  success,  although,  in  spite  of 
Halsted's  dictum,  I  do  not  think  the  existence  of  a  normal 
pituitary  would  do  so. 

Schafer  also  tried  the  effect  of  grafts  from  the  posterior  lobe, 
and  observed  a  temporary  and  moderate  polyuria.  As  the  graft 
disappeared  so  did  the  increase  in  the  quantity  of  urine  secreted. 
No  doubt  so  long  as  any  infundibular  secretion  remains  to  be 
extracted  from  the  graft  the  effect  mentioned  may  be  observed, 
if  the  extract  of  the  pars  nervosa  causes  diuresis  :  but  when  all 
this  is  absorbed  there  will  be  a  return  to  the  previous  state. 

Allusion  has  already  been  made  to  Cushing's  apparently 
successful  implantation  of  a  homoplastic  graft  in  the  human 
subject. 

It  is,  however,  clear  that  the  small  amount  of  work  which 
has  been  done  on  implantation  of  the  pituitary  has  not  proved 
satisfactory ;     but    it    is    also    apparent   that    various    necessary 

1  Crowe,  S.  J.,  H.  Gushing,  and  J.  Homans,  Bull.  Johns  Hopk.  Hosp.,  1910. 
xxi,  127. 

2  Schafer,  E.  A.,  Proc.  Boy.  Soc.  Biol,  1909,  lxxxi,  Ser.  B.  442. 


122  PHYSIOLOGY 

conditions,   already  mentioned,   have  not  always  been  carefully 
observed. 

The  subject  is  an  important  one,  for  in  the  future  the  success 
of  some  of  the  surgical  procedures  practised  in  connexion  with 
the  pituitary  body  may  depend  on  satisfactory  implantations. 


LATE    RESULTS    OF    INJECTION    AND    INGESTION 

Schafer1  has  investigated  the  effects  of  feeding  with  anterior 
lobe,  and  Cerletti2  of  injecting  an  emulsion  into  the  peritoneal 
cavity. 

Schafer's  experiments  were  not  very  conclusive,  but  they 
tended  to  show  that  there  is  more  rapid  increase  in  the  weight 
of  animals  receiving  an  extract  of*  the  anterior  lobe  than  of  the 
controls.  Cerletti  found  retardation  in  the  growth  of  bones  in 
the  animals  to  which  the  extract  was  administered  ;  but  his 
control  experiments  have  been  considered  unsatisfactory. 

Metabolism  experiments  under  these  conditions  have  been 
carried  out  by  various  observers,  but  the  results  obtained  have 
been  most  conflicting.  Oswald3  administered  an  extract  of 
the  whole  gland  by  the  mouth  to  dogs,  but  observed 
no  effect  on  the  nitrogen  and  phosphorus  excretions.  Malcolm4 
in  a  series  of  experiments  came  to  the  following  conclusions. 
The  administration  of  dried  pars  anterior  causes  retention  of 
nitrogen  and  phosphorus.  Dried  pars  nervosa  (?  posterior  lobe) 
produces  the  same  effect.  Fresh  entire  gland  produces  an 
opposite  effect  in  regard  to  the  nitrogen.  The  dried  partes 
anterior  and  nervosa  (?  posterior)  both  cause  an  increased  output 
of  calcium ;  but  the  former  also  brings  about  a  large  excretion 
of  magnesium  in  the  fasces,  while  the  pars  nervosa  does  not 
do  so  to  the  same  extent.  The  same  investigator  found  that 
the  fresh  gland  has  no  influence  on  the  calcium  output  when 
the  animal  is  on  a  calcium-poor  diet,  but  rather  a  tendency 
in  the  opposite  direction.  The  excretion  of  magnesium,  however, 
is   increased. 

1  Schafer,  E.  A.,  Proc.  Roy.  See.  Biol,  1909,  lxxxi,  Ser.  B.  442. 

2  Cerletti,  U.,  Arch.  Hal.  d.  Biol,  1907,  xlvii,  123. 

3  Oswald,  A.,  Virchow's  Arch.,  1902,  clxix,  444. 

4  Malcolm,  J.,  Journ.  Physiol,  1904,  xxx,  270. 


LATE   RESULTS    OF   INJECTION   AND    INGESTION     123 

Franchini1  observed  that  there  is  a  reduction  in  the  calcium, 
magnesium,  and  phosphorus  metabolism  in  animals  fed  with  an 
extract  of  the  whole  gland.  Wasting,  intestinal  ulceration  and 
cardiac  hypertrophy  were  also  seen. 

Thompson  and  Johnson2  found  that  whole-gland  pituitary 
extract  stimulates  the  metabolism  in  the  dog  in  an  increasing 
degree  even  when  the  dose  is  not  increased.  This  is  shown  in 
the  output  of  nitrogen,  urea  and  the  phosphates,  and  also  by  the 
loss  of  body-weight. 

Schafer  and  Vincent3  found  that  subcutaneous  injections 
given  over  a  length  of  time  produce  marked  toxic  effects  :  there 
is  quickened  respiration  and  increased  pulse-rate,  associated 
ultimately  with  paralysis  beginning  in  the  hind  legs.  Glycosuria 
and  diuresis  are  almost  constant  symptoms  in  rabbits  ;  and 
Thaon4  has  recorded  hematuria  as  a  late  result. 

Carraro5  observed  that  hepatic  degeneration  with  necrosis  of 
the  liver-cells  occurs  after  long  continued  injections  of  infundib- 
ulin. 

Conti  and  Curti6  state  that  the  toxic  symptoms  following 
injections  of  pituitary  extracts  are  ameliorated  by  the  previous 
injection  of  thyroid  extract  or  of  an  extract  of  the  pituitary 
itself. 

Rosalind  Wulzen7  found  that  the  growth  of  a  young  fowl 
is  retarded  by  the  addition  to  the  diet  of  fresh  unmodified 
anterior  lobe  of  ox's  pituitary.  This  was  shown  in  the  body- 
weight  and  the  diminished  growth  of  the  long  bones.  She  also 
noted  involution  of  the  thymus.  All  these  changes  were  more 
marked  in  males  than  in  females.  The  results  obtained  appeared 
to  be  dependent  to  some  extent  on  the  dosage  employed. 

With  regard  to  the  renal  excretions,  Carlson  and  Martin8, 
referring  to  the   work   of    Borchardt9   and   of   Goetsch,    dishing 


1  Franchini,  G.,  Berl.  Klin.  Woch.,  1910,  xlvii,  613,  670,  and  719. 

2  Thompson,  W.  H.,  and  H.  M.  Johnson,  Journ.  Physiol,  1905-6,  xxxiii,  189. 

3  Schafer,  E.  A.,  and  S.  Vincent,  Journ.  Physiol,  1899-1900,  xxv,  87. 

4  Thaon,  P.,  Lliypophyse,  Paris,  1907. 

5  Carraro,  A.,  Arch.  p.  le  Sci.  Med.,  1908,  xxxii,  42. 

6  Conti,  A,  and  O.  Curti,  Boll.  Sci.  Med.  di  Bologna,  1906,  viii,  629. 

7  Wulzen,  R.,  Amer.  Journ.  Physiol,  1914,  xxxiv,  127. 

8  Carlson,  J.,  and  L.  M.  Martin,  Amer.  Journ.  Physiol,  1911,  xxix,  64. 

9  Borchardt,  L.,  Zeitsch.  f.  Klin.  Med.,  1908,  Ixvi.  332. 


124  PHYSIOLOGY 

and  Jacobson1,  which  seemed  to  show  that  injections  of  the 
posterior  lobe  may  cause  hyperglycemia  and  glycosuria,  assert 
that  cerebrospinal  fluid,  which  according  to  Gushing  and  others 
contains  infundibulin,  has  no  such  effect  in  meat-fed  dogs. 

Carlson  and  Martin  also  state  that  intravenous  injections 
of  large  quantities  of  extracts  of  both  lobes  of  the  pituitary  do 
,  not  give  rise  to  sugar  in  the  urine — even  though  pushed  until 
toxic  symptoms,  such  as  vomiting  and  purgation,  appear. 

Goetsch2  has  quite  recently  made  some  extensive  investiga- 
tions concerning  the  influence  of  feeding  with  pituitary  extracts 
upon  growth  and  sexual  development ;  and  he  has  come  to  the 
following  conclusions. 

A  dried  and  powdered  extract  of  the  posterior  lobe  causes 
failure  to  gain  in  weight,  loss  of  appetite,  increased  peristalsis 
with  enteritis,  muscular  tremors  and  weakness  of  the  hind  limbs. 
The  same  effects  are  observed  after  the  administration  of  ex- 
cessive doses  of  whole-gland  preparations,  owing  to  the  extract 
of  the  pars  posterior  contained  therein. 

The  administration  of  dried  and  powdered  pars  anterior 
causes  an  increase  in  the  rate  of  growth,  and  early  sexual  develop- 
ment in  the  young  animal. 

I  myself  have  investigated  the  late  effects  on  a  few  adult 
female  animals  of  injections  of  extracts  made  from  the  pars 
anterior  and  the  pars  posterior  ;  but  no  metabolism  experiments 
were  carried  out.     I  obtained  the  following  results. 

Two  guinea-pigs  which  received  on  alternate  days  20  in- 
jections of  0*5  c.c.  of  an  extract  of  the  pars  anterior  lost  a  little 
weight  :  one  animal  weighing  300  grammes  was  found  to  weigh 
270  grammes  at  the  end  of  the  experiment  ;  and  the  other, 
which  originally  weighed  310  grammes,  ultimately  weighed  290 
grammes.  Such  slight  losses  in  weight  may  have  been  due  to  the 
general  disturbance  caused  by  the  injections.  A  third  animal, 
which  was  found  dead  after  the  seventh  injection,  weighed  500 
grammes  at  the  beginning  of  the  experiment,  and  only  450 
grammes  at  the  end. 

Three  guinea-pigs  which  received  0*1  c.c.  of  infundibulin 
all    gained   in    weight.     One    weighing    430    grammes    ultimately 

1  Goetsch,  E.,  H.  Gushing,  and  C.  Jacobson,  Bull.  Johns  Ilopk.  Hosp.,  1911, 
xxii,  165. 

2  Goetsch  E.,  Bull.  Johns  HopL  Hosp.,  1916,  xxvii,  129. 


LATE   RESULTS   OF    INJECTION   AND    INGESTION     125 

weighed  500  ;  another  of  300  grammes  increased  to  330 
grammes ;  and  the  weight  of  the  third  rose  from  280  grammes 
to  300  grammes.  Three  other  animals  died  on  the  same  date 
after  receiving  18  injections  each,  and  in  all  probability  they 
died  of  some  intercurrent  affection.  These  three  guinea-pigs, 
also,  had  increased  in  weight  :  the  first  from  270  to  280 
grammes  ;  the  second  from  400  to  420  grammes ;  and  the  third 
from  220  to  240  grammes.  In  no  case  were  the  doses  pushed 
to  lethal  quantities  ;  but  with  the  quantities  used,  which  were 
not  small  in  proportion  to  the  body-weight,  no  other  definite 
changes  were  detected  in  the  condition  of  the  animals,  nor  were 
obvious  symptoms  produced. 

In  one  case  a  virgin  guinea-pig  was  fed  daily  with  0'5  gramme 
of  pars  anterior  for  45  days,  then  with  1*0  gramme  for  14  days, 
and  finally  with  2'0  grammes  for  50  days.  This  animal  increased 
in  weight  from  390  grammes  to  420  grammes. 

In  all  cases  complete  post-mortem  examinations  were  con- 
ducted on  the  animals,  whether  they  died  or  were  killed  ;  and 
special  attention  was  directed  to  the  histological  appearances  of 
the  reproductive  organs  and  of  the  hormonopoietic  glands.  Only 
in  the  case  of  the  pituitary  was  any  definite  change  observed. 
This  occurred  in  the  two  guinea-pigs  that  received  20  injections 
of  an  extract  of  the  pars  anterior.  In  both  cases  the  pars 
anterior  of  the  pituitary  showed  only  chromophobe  cells,  which 
were  arranged  in  acinous  formation.  In  all  the  other  cases, 
including  the  animal  which  was  fed  with  dried  anterior  lobe,  the 
pituitaries  were  normal  in  regard  to  the  differential  staining 
of  the  cells. 

It  is,  perhaps,  also  worthy  of  mention  that  colloid  was  some- 
what excessive  in  quantity  in  the  thyroids  of  the  animals  which 
received  injections  of,  and  of  the  one  which  was  fed  with,  extract 
of  the  pars  anterior. 


§  ii.  PATHOPHYSIOLOGICAL  INVESTIGATIONS 


OPERATIONS    ON    THE    PITUITARY 

Of  the  two  methods  of  eradication — destruction  in  situ  and 
removal — the  latter  is  preferable,  for  it  is  impossible  in  applying 
the  actual  cautery  or  caustics  to  limit  the  sphere  of  action,  or 
exactly  to  destroy  different  parts  of  the  pituitary  body.  Even 
when  complete  destruction  is  desired  it  cannot  be  said  with 
certainty,  although  the  pituitary  may  have  been  destroyed,  that 
the  lesion  is  confined  to  that  organ. 


DESTRUCTION    OF    THE    PITUITARY 

Destruction  of  the  pituitary  in  situ  has  been  attempted  many 
times  by  means  of  the  actual  cautery,  by  caustics,  such  as 
chromic  acid  (Marienesco1 ;  Vassale  and  Sacchi2 ;  Fichera3), 
and  by  '  needling  '  (Lomonaco  and  Rynberg4 ;  Gaglio5).  The 
oral  route  through  the  basisphenoid  has  been  the  method  of 
access  usually  employed  in  the  former  procedures,  and  occa- 
sionally the  vertical  route  for  destruction  of  the  pituitary  by 
needling. 

A  more  interesting — if  equally  doubtful — method  of  destruc- 
tion  was   that   of   Masay6   who   used   a   cytotoxic.     He   thought 

1  Marienesco,  G.,  Compt,  Rend,  Soc.  Biol,  1892,  xliv,  509. 

2  Vassale,  G.,  and  E.  Sacchi,  Riv.  Sper.  di  Freniat.,  Reggio-Emilia,  1892,  xviii, 
525. 

3  Fichera,  G.,  Sper.  Arch,  di  Biol,  1905,  lix,  739. 

4  Lomonaco,  D.,  and  R.  van  Rynberg,  Atti  Accad.  dei  Lincei,  1901,  x,  117, 
212  and  265. 

5  Gaglio,  G,  Arch.  Ital  d.  Biol,  1902,  xxxviii,  117. 

6  Masay,  F.,  Uhypophyse,  Bruxelles,  1908. 


REMOVAL    OF   THE   PITUITARY  127 

a  specific  reaction  was  obtained  as  the  result  of  his  experi- 
ments, associated  with  histological  changes  in  the  pituitary  ;  but 
as  the  group  of  symptoms  produced  included  wasting,  it  can 
hardly  be  conceded  that  specific  pituitary  insufficiency  was  pro- 
duced, for  it  has  been  almost  conclusively  proved  that  this  state 
is  associated  with  adiposity. 


REMOVAL   OF    THE    PITUITARY 

The  first  experimental  removals  were  undertaken  by  Victor 
Horsley1 ;  but  most  of  the  animals  died  soon  after  opera- 
tion, and  very  little  information  was  obtained.  Later  Caselli2, 
Friedmann  and  Maas3,  Vedova4  and  many  others — too  numerous 
to  mention — attempted  extirpation  by  various  procedures  and 
routes,  but  were  unsuccessful  in  obtaining  satisfactory  results. 

The  methods  of  access  employed  were  generally  either  the 
temporal  route,  or  more  commonly  the  oral.  In  the  former 
the  temporal  bone  was  widely  removed  and  the  temporal  lobe 
of  that  side  raised,  in  order  that  the  operator  might  reach  the 
base  of  the  brain.  In  the  oral  route  the  basisphenoid  was  per- 
forated and  the  pituitary  body  scraped  out  with  a  spoon.  At- 
tempts have  also  been  made  to  deal  with  the  pituitary  in  animals 
by  reaching  it  through  the  frontal  fossa.  In  this  method  the 
frontal  lobe  is  raised,  much  in  the  same  way  as  that  adopted 
for  the  temporal  lobe  in  the  lateral  operation. 

It  is  quite  obvious  that  in  animals  the  anterior  route  has 
incomparably  less  advantage  than  the  lateral,  and  that  the  oral 
route  through  the  basisphenoid — apart  from  creating  an  open 
door  for  sepsis — is  somewhat  of  a  shot  in  the  dark,  for  the 
operator  can  have  no  possible  idea  of  what  he  is  actually 
removing.  These  remarks  concerning  the  basisphenoidal  route 
refer  to  experimental  work,  and  do  not  apply  to  operations 
on  the  human  subject,  in  whom  decompression  alone  through 
the    floor   of    the    sella    turcica  by  the   nasal    (not    oral)   route 

1  Horsley,  Victor,  Lancet,  1886,  i,  5. 

2  Caselli.  A.,  Biv.  Sper.  di  Frt  nidi.,  Beggio-Emilia,  1900,  xxvi,  176  and  486. 

3  Friedmann,  F.  F.,  and  O.  Maas,  Bert  Klin.   Wnch.,  1900,  xxxvii,  1213. 

4  Vedova,  Dalla,  Boll.  Accad.   Med.    di  Boma,   1903,    xxix,   150;    idem    l!i<>4, 
xxx,  137. 


128  PHYSIOLOGY 

may  produce  satisfactory  results  in  certain  lesions  of  the 
pituitary. 

All  the  earlier  experiments  were,  therefore,  more  or  less  com- 
plete failures  ;  and  it  was  not  until  the  more  recent  work  of 
Paulesco1  who,  with  the  aid  of  a  surgical  colleague,  evolved  the 
procedure  known  as  the  bitemporal  method,  that  successful 
operations  were  accomplished,  and  reliable  results  obtained. 
Nevertheless,  the  published  accounts  of  operations  experimentally 
performed  on  the  pituitary  by  the  newer  method  of  approach 
are  still  surprisingly  few.  It  is  probable  that,  apart  from  the 
investigations  of  Paulesco  (1908),  of  Harvey  Cushing  and  his 
colleagues  (1909,  1910),  and  possibly  also  of  Silbermark  (1910), 
Biedl  (1910)  and  Ascoli  and  Legnani  (1912),  no  successful  work 
has  been  carried  out.  Further,  although  Victor  Horsley  (1886) 
was  certainly  the  first  to  perform  extirpation  experiments  in 
this  country,  and  probably  in  the  world,  there  do  not  appear 
to  have  been  any  attempts  either  by  surgeons  or  physiologists,  in 
Great  Britain — apart  from  later  experiments2  by  the  operator 
just  mentioned — to  conduct  investigations  on  these  lines  until 
those  recorded  in  the  year  19173. 

My  experiments  were  concerned  not  only  in  an  attempt  to 
gain  further  information  in  regard  to  the  experimental  pathology 
of  the  pituitary,  but  also  in  testing  the  correctness  or  otherwise 
of  the  experiments  of  Paulesco4,  and  of  Cushing  and  his  fellow- 
workers4,5. 

I  shall  first  give  a  somewhat  full  account  of  my  own  work, 
as  this  has  only  recently  been  published  and  as  so  little  has  been 
done  on  the  subject,  also  in  the  hope  that  my  experiences 
may  assist  others  to  conduct  fresh  investigations  which  are 
urgently  needed.  Afterwards,  I  shall  discuss  together  all  the 
results  obtained  by  the  improved  methods  of  technique  since 
Paulesco  entered  this  interesting  field  of  investigation. 

1  Paulesco,  N.  C,  Dhypophyse  du  cerveau,  Paris,  1908. 

2  Handelsmann  (no  initial  in  original),  and  V.  Horsley,  Brit.  Med.  Journ.,  1911, 
ii,  1150. 

3  Bell,  W.  Blair,  Quart.  Journ.  Exper.  Physiol,  1917,  xi,  78. 

4  Reford,  L.  L.,  and  H.  Cushing,  Bull.  Johns  Hopk.  Hosp.,  1909,  xx,  105. 

5  Crowe,  S.  J.,  H.  Cushing,  and  J.  Homans,  Bull.  Johns  Hopk.  Hosp.,  1910, 
xxi,  127. 


REMOVAL   OF   THE   PITUITARY  129 

Operative   technique 

In  my  experiments  27  bitches  were  subjected  to  operation, 
and  of  these  two  died  as  the  result  of  the  operative  procedures, 
as  distinct  from  the  actual  lesions  produced  in  the  pituitary. 
Only  one  of  the  deaths  could  be  attributed  to  faulty  surgical 
technique,  and  in  this  case  the  operation  was  abandoned  owing 
to  haemorrhage  from  which  the  animal  succumbed  shortly  after- 
wards. The  other  immediate  death  was  due  to  an  overdose  of 
ether  before  the  completion  of  the  operation.  Another  animal 
died  soon  after  total  extirpation  of  the  pituitary  from  some 
unknown  cause — possibly  from  an  overdose  of  the  anaesthetic. 
All  the  other  cases  did  well  so  far  as  the  operative  procedures 
were  concerned. 

Excluding,  then,  the  two  bitches  that  died  before  the  com- 
pletion of  the  operation,  25  cases  are  left  for  consideration 
(tables  II-X). 

Most  of  the  animals  used  were  from  four  to  seven  months 
old,  but  a  few  were  a  little  older.  The  younger  the  dog  is,  the 
easier  the  operation,  owing  to  the  thinness  of  the  skull  and  lesser 
risk  of  serious  intracranial  haemorrhage. 

Preliminary  procedures. — For  ten  days  previously  to  the 
principal  operation  the  animal  received  daily  10  grains  of  forma- 
mine  in  the  food,  in  order  that  the  cerebrospinal  fluid  might  be 
rendered  antiseptic,  as  advised  by  Crowe1. 

Anaesthesia  was  produced  with  ether  by  the  '  open  '  method 
a  few  days  before  the  operation  on  the  pituitary,  and  a  small 
portion  of  one  uterine  horn  together  with  part,  or  the  whole, 
of  the  ovary  on  the  same  side  were  removed  through  a  lateral 
abdominal  incision  for  the  purpose  of  control  observations  in 
connexion  with  subsequent  changes  in  the  genitalia.  At  the 
conclusion  of  this  operation  the  whole  of  the  top  of  the  head  and 
back  of  the  neck  was  closely  shaved,  in  order  to  lessen  the  time 
occupied  at  the  second  operation.  In  those  cases  in  which  a 
fatal  result  was  anticipated — except  in  the  case  of  bitch  no.  19 — 
the  removal  of  portions  of  the  genitalia  was  not  practised,  but 
the  preliminary  shaving  was  always  effected. 

Method   of  producing  ancesthesia. — In   view   of    the   difficulty 
of  working  aseptically  and  comfortably  (hiring  the  operation  on 
1  Crowe,  S.  J.,  Bull.  Johns  Hopk.  Hosp.,  1909,  xx,  102. 

9 


ISO 


PHYSIOLOGY 


the  pituitary  in  close  proximity  to  the  administrator,  if  the 
anaesthetic  were  given  in  the  ordinary  way,  I  decided  to  use 
an  intratracheal  method  for  the  administration  of  ether.  This 
was  found  to  be  ideal  after  we  had  overcome  the  initial  diffi- 
culties, which  caused  us  to  lose  certainly  one  and  possibly  two 
out  of  the   first  three   animals   submitted   to   operation.     In  all 


Fig.  81. 

Apparatus  for  the  administration  of  intratracheal  ether.  (Photograph.)  A,  tube 
from  bellows  ;  B,  indicator  of  three-way  tap ;  C,  tube  to  ether-container ;  D,  ether- 
container  ;  E,  tube  from  ether-container ;  F,  tube  to  mercurial  pressure- valve ;  G, 
mercurial  pressure- valve ;  H,  pressure-manometer ;  I,  tube  to  catheter ;  K,  catheter. 

the  subsequent  cases  the  anaesthesia  was  smooth,  uninter- 
rupted and  safe,  and  the  animal  was  easily  restored  to  conscious- 
ness as  soon  as  the  operation  was  completed  by  the  administra- 
tion of  air  alone  through  the  intratracheal  tube. 

In   figure    81    the   apparatus   used    is    illustrated.      It   is    an 
easily   made   adaptation   of   the   more   complicated   machines   in 


REMOVAL    OF   THE    PITUITARY  131 

general  use  for  the  intratracheal  administration  of  ether  to  the 
human  subject.  Practice  may  be  required  in  passing  the  soft 
rubber  catheter  into  the  trachea.  The  size  of  the  catheter  is 
determined  by  the  diameter  of  the  animal's  trachea,  which  the 
catheter  should  never  fit  closely.  The  insertion  of  the  catheter 
was  effected  after  the  animal  had  been  anaesthetized  with  ether 
by  the  ordinary  '  open  '  method. 

During  the  intratracheal  administration  of  the  anaesthetic  the 
animal  rarely  received  concentrated  ether-vapour  :  it  was  usually 
sufficient,  once  the  animal  was  fully  anaesthetized,  to  continue 
the  anaesthesia  with  a  mixture  of  air  and  ether-vapour,  regu- 
lated by  means  of  a  three-way  tap  to  which  an  indicator  was 
attached  (fig.  81,  B).  By  this  means  ether,  ether  and  air  mixed, 
or  air  alone  could  be  pumped  into  the  lungs  under  uniform 
and  limited  pressure. 

The  anaesthetist  sat  at  the  side  of  the  table  opposite  to  the 
operator  with  his  hand  underneath  the  covering  cloth  and  rest- 
ing against  the  side  of  the  animal,  in  order  to  judge  of  its  con- 
dition :  quiet,  deep  and  slow  respiration  indicated  perfect  anaes- 
thesia ;  rapid,  shallow  breathing  too  deep  anaesthesia ;  while 
insufficient  anaesthesia  was  shown  by  jerky  and  spasmodic 
respiration,  or  even  by  the  animal  coughing.  The  heart-beat 
also  gave  an  indication  of  the  condition  of  the  subject. 

Surgical  procedures. — The  animal,  completely  under  the 
influence  of  ether-vapour  administered  intratracheally,  was 
placed  on  its  belly  on  an  electrically  heated  table  with  the  chin 
resting  on  a  V-shaped  depression  cut  out  of  a  solid  block  of  wood 
(fig.  82).  The  legs  were  fixed  to  the  sides  of  the  table,  and  the 
ears  were  tied  together  across  the  throat  by  means  of  a  silk 
suture  passed  through  the  tips.  Next,  the  eyes  were  carefully 
protected  with  dabs  while  the  previously  shaven  scalp  was 
thoroughly  purified  with  iodine  dissolved  in  chloroform  or  spirit. 
The  animal  was  then  entirely  covered  with  a  sterilized  sheet, 
in  which  there  was  a  small  aperture  through  which  the  opera- 
tion was  conducted  (fig.  83).  The  special  sliding  instrument- 
table  attached  to  the  operating-table  (fig.  82)  was  also  com- 
pletely covered  with  a  sterilized  cloth  (fig.  83). 

A  long  incision,  extending  backwards  from  the  root  of  the 
nose  in  the  mid-line  over  the  vault  of  the  skull  as  far  as  the 
occipital    protuberance,    was    carried   downwards     and    laterally 


132 


PHYSIOLOGY 


View  of  operating-table,  showing  also  the  sliding  instrument-table,  the 
V-shaped  block  for  animal's  head,  and  the  tube  leading  to  the  ether  apparatus. 
{Photograph.) 


Fig.  83, 

View  of  operating-table  and  sliding  instrument-table  covered  with  sterile 
cloths,  as  at  the  commencement  of  the  operation.     {Photograph.) 


REMOVAL    OF   THE    PITUITARY 


133 


behind  the  ear  on  the  side  from  which  the  approach  to  the 
pituitary  was  to  be  made  (fig.  84).  This  incision  was  found  to 
be  better  than  the  Y-shaped  incision  which  was  adopted  by 
dishing  and  others,  and  which  I,  also,  employed  in  the  first  few 
operations. 

Next,   the   skin   over  the  right  temporal  region   was   turned 


Fig.  84-. 
view  of  a  bitch's  head,  showing  the  line  of  incision.     (Photograph.) 


xi 


down,  and  the  temporal  muscle  and  pericranial  fascia  were 
carefully  reflected  from  the  underlying  temporal  bone,  which 
was  removed  widely  with  a  trephine  and  rongeur.  The  dura 
mater  was  opened  with  a  triradiate  incision,  care  being  taken 
to  avoid  the  vessels  (fig.  85).  The  muscle-flap  was  then  loosely 
replaced  together  with  the  overlying  skin,  and  attention  was 
turned   to  the   other   side   from   which  the   major   portion   of  the 


134 


PHYSIOLOGY 


operation  was  to  be  conducted  :  in  my  experiments  this  was 
always  on  the  left  side  of  the  animal.  The  skin  overlying  the 
temporal  region  was  raised  on  this  side  until  the  zygomatic  arch 
was  exposed.  This  structure  was  excised,  together  with  the 
overlying  aponeurosis,  with  a  pair  of  bone-cutting  forceps.  The 
temporal  muscle  was  reflected  as  on  the  right  side,  and  the  temp- 
oral   bone   widely   removed   with    a    trephine    and   rongeur   (fig. 


Fig.  85. 

View  of  the  field  of  operation  at  the  stage  when  the  bilateral  openings  have 
been  made  in  the  skull. 

85).  On  this  side,  however,  care  was  taken  that  the  aperture 
made  extended  down  as  far  as  possible  to  the  base  of  the  skull. 
If  there  were  any  bleeding  from  the  bone  on  either  side  it  was 
readily  stopped  with  bone-wax. 

In  figure  86  is  seen  a  skiagram  of  the  skull  of  one  of  the 
animals  taken  during  life  a  few  weeks  after  operation  :  the 
large  aperture  made  on  the  left  side  is  clearly  shown. 


REMOVAL   OF   THE   PITUITARY 


185 


. 


Fig.  86. 


Radiograph  of  bitch's  head  taken  during  life  some  weeks  after  operation,  showing 
the  large  aperture  made  in  the  left  side  of  the  skull.     (By  Thurstan  Holland.) 


Fig.  87. 
Soft  metal  spoon-shaped  brain-retractor.     (Photograph.) 


x|. 


136 


PHYSIOLOGY 


A  head-light  was  now  required  ;  and  the  next  steps  of  the 
operation  were  conducted  by  the  operator  single-handed,  for  it 
was  necessary  to  manage  the  brain-retractor 
with  one  hand,  while  the  manipulations  in 
connexion  with  the  pituitary  were  carried  out 
with  the  other.  It  will  be  evident,  therefore, 
that  as  no  assistant  is  really  required  for  the 
initial  and  later  stages,  these  operations  can 
easily  be  performed  without  help  ;  but,  in 
order  to  expedite  matters,  such  as  the 
cutting  of  ligatures,  an  assistant  is  desirable. 
The  brain — that  is,  the  temporal  lobe  on 
the  left  side — was  carefully  elevated  with 
the  special  spoon-shaped  retractor  (fig.  87) 
recommended  by  dishing.  As  soon  as 
the  temporal  fossa  had  been  crossed  a 
thickened  ridge  of  dura  mater  attached  to 
the  inner  limit  was  seen.  This  marks  the 
outer  edge  of  the  sella  turcica,  or  rather  the 
fossa  to  the  edge  of  which  the  dura  is 
attached,  and  of  which  the  sella  turcica  is 
the  most  dependent  part.  The  long,  hooked 
knife  (fig.  88)  was  then  taken,  and  a  slit 
made  in  the  dura  mater  above  the  lower 
attachment  just  mentioned.  Care  was  taken 
to  carry  the  incision  forwards  rather  than 
backwards  in  order  to  avoid  wounding  a 
large  vessel  frequently  encountered  in  the 
dura  mater.  When  the  tip  of  the  retractor 
was  passed  through  the  opening  thus  made, 
a  white  glistening  ridge  or  strand  of  rein- 
forced dura  was  disclosed,  and,  when  the 
beak  was  tilted  upwards,  the  third  nerve 
Long, hooked  knife  passing  from  behind  forwards  and  above 
for  incising  the  dura    downwards    was    brought    into    view,    and   in 

mater.      (Photograph. )  b 

x  f    front    of   this    the    carotid    artery.       Between 

these    two    structures,    but    further    in,    the 

pituitary  body  was   exposed   (fig.    89).       This    organ    was    easily 

recognized    by  its    typical    apricot-like    colour,    which    is   due  to 

the    extreme  vascularity   of   the    anterior    lobe.      All    blood    and 


Fig.  88. 


REMOVAL   OF   THE   PITUITARY 


137 


cerebrospinal  fluid  was  now  mopped  out  with  small  dabs 
of  wool  held  in  forceps  bent  at  an  angle  (fig.  90).  As  soon 
as  the  field  was  dry  the  rest  of  the  operation  planned  was 
carried  out. 

Most    of  my  operations  consisted  in  the  removal  of  portions 
of  the  pituitary.     I  used  for  this  purpose  a  special  pair  of  aural 


Fig.  89. 


View  of  the  field  of  operation  at  the  stage  when  the  pituitary  is  first  exposed.     The 
circle  of  light  from  the  head-lamp  is  seen  in  the  centre  of  the  field. 


forceps  (fig.  91),  which  I  found  very  convenient.  It  was  im- 
possible to  obtain,  or  have  made,  an  instrument  with  spoon- 
beaks  which  were  large  enough  to  contain  the  pituitary  body 
and  which  at  the  same  time  could  be  opened  widely.  With 
the  instrument  mentioned  I  was  able  to  remove  in  several  frag- 
ments most  of  the  anterior  lobe,  and  practically  the  whole  of 
the    posterior    lobe    intact.      To   remove   the   entire   pituitary   I 


138 


PHYSIOLOGY 


Fig.  90. 


Angular  forceps  for  holding  wool  dabs  with  which  the  cerebrospinal  fluid  and 
blood  are  mopped.      {Photograph.) 


Xf. 


Fro.  91. 
Aural  forceps  for  removing  portions  of  the  pituitary.      (Photograph.) 


Xi. 


Fig.  92. 

Author's  chisel-hook  for  cutting  through  the  stalk  of  the  pituitary.     (Photograph.) 


REMOVAL   OF   THE    PITUITARY 


139 


had  a  special  instrument  made  :  this  consists  of  a  lower  blade 
terminating  in  a  blunt  hook  in  which  the  stalk  of  the  pituitary 
is  caught  ;  the  upper  blade,  which  is  formed  like  a  chisel  but  is 
blunt,  can  be  pushed  in,  so  as  to  cut  through  the  stalk  caught 
in  the  hook  (fig.  92).  The  lower  attachments 
of  the  pituitary  were  always  first  separated 
with  a  fine  blunt  Watson-Cheyne's  dissector 
(fig.  93),  before  the  stalk  was  cut  through  ; 
after  this  the  pituitary  could  be  lifted  out 
with  a  pair  of  bent  forceps.  This  freeing  of 
the  lower  attachments  of  the  pituitary  was 
found  advisable  in  all  operations  except  those 
in  which  the  stalk  was  separated  or  clamped, 
or  in  which  an  artificial  tumour  was  in- 
troduced. 

The  operation  was  completed  by  the 
sewing  of  the  temporal  muscles  in  place 
and  the  closure  of  the  incision  through  the 
skin. 

Alarming  haemorrhage  sometimes  occurred 
during  the  operation,  especially  in  the  older 
animals,  but  in  all  except  one  case  this  was 
controlled  without  difficulty ;  and  probably 
there  was  a  little  carelessness  in  the  case 
that  was  lost,  for  we  had  been  accustomed 
easily  to  check  the  haemorrhage  with  plugs 
of  wool,  and  had  come  to  regard  it  as 
of  small  consequence.  Nevertheless,  the 
operation  was  found  to  be  much  less  for- 
midable .than  the  previous  descriptions  of 
it  led  us  to  expect.  The  average  time 
occupied  by  the  actual  operations  was  39 
minutes. 

The  final  determination  of  the  character 
of  the  operation  in  the  extirpation  experi- 
ments was  made  in  every  case  by  a  careful  comparison  of  the 
tissue  removed  at  operation  with  the  post-mortem  histological 
findings. 

As   it   seems   hardly    worth    while   reduplicating  the   illustra- 
tions which  show  more  or  less  identical  results,  only  those  have 


/ 

Pig.  93. 

Watson -Cheyne's  dis- 
sector.    (Photograph.) 


140  PHYSIOLOGY 

been  reproduced  which  illustrate  most  clearly  the  findings  that 
may  be  considered  typical  and  important. 

Postoperative  symptoms. — In  no  case  were  there  severe  com- 
plications, such  as  serious  sepsis  and  paralyses,  as  the  result  of 
the  operative  procedures  ;  but  sometimes  there  was  an  escape 
of  cerebrospinal  fluid  from  the  wound.  Generally,  the  animals 
drank  milk  within  a  few  hours  of  the  operation,  and  seemed  little 
affected  the  next  day,  when  they  ate  meat,  and  were  able  to  get 
out  of  their  beds  and  walk  about. 

Of  the  genera]  symptoms  following  operations  on  the  pituitary, 
polyuria  and  glycosuria  are  not  infrequent1 — except  after  imme- 
diately lethal  procedures  when  there  may  be  anuria— and  these 
phenomena  are  probably  due  to  the  action  of  glycogenetic  and 
diuretic  substances  liberated  from  the  pars  posterior. 

With  respect  to  the  cachexia  said  by  Cushing  to  be  specific 
in  connexion  with  certain  pituitary  lesions,  I  have  been  unable 
to  verify  his  conclusions,  and  I  am  of  the  opinion  that  the 
supposed  typical  posture  attributed  to  the  so-called  '  cachexia 
hypophyseopriva  '  (see  fig.  112,  p.  173)  is  merely  an  attitude  of 
weakness,  which  is  always  seen  in  dogs  in  an  advanced  stage  of 
emaciation  and  debility  from  any  cause  whatsoever. 

I  shall  discuss  later  the  curious  somnolence  which  may  over- 
take the  animals  after  some  of  these  operations. 

Control   experiments 

These  were  two  in  number,  and  in  both  cases  the  bitches 
were  submitted  to  the  same  general  procedures  as  those  adopted 
in  the  other  experiments,  even  to  the  previous  removal  of  a 
portion  of  the  uterus  and  ovary.  The  pituitary  body  was 
exposed  at  the  second  operation,  but  no  part  of  it  was 
removed  ;  instead,  small  pieces  of  tissue  were  excised  from  the 
base  of  the  brain  in  the  neighbourhood.  Neither  of  these 
animals  showed  any  symptom  until  shortly  before  death,  when 
one  of  them  died  with  convulsions.  This  animal  was  probably 
poisoned,  for  another  bitch  which  was  chained  up  next  to  her 
died  with  convulsions  at  the  same  time.  In  both  cases  death 
occurred  many  months  after  operation,  and  in  neither  was 
any  causal  lesion  found   in   the  brain. 

1  Cushing,  H.,  Boston  Med.  and  Surg.  Journ.,  1913,  clxviii,  901. 


REMOVAL    OF   THE   PITUITARY 


141 


In  table  II  are  given  the  details  of  these  control  experiments. 
One  of  the  bitches  (no.  9)  before  and  152  days  after  operation  is 
shown  in  figures  94a  and  94b.  There  was  no  change  in  the  animal 
except  some  increase  in  size  corresponding  with  the  increase  in  age. 


Table  11. — Control  Experiments. 


2 

si 

s 

o  o 

—  o  5   ■ 

•till 

"rt  S 

P.M.  findings. 

as 

"0  a> 

2  a 

S3 

<—  p. 

3  ■§  £  2 

i  -i  ~  i 

Z  —    j    Pi 

a  a  - 

o 

£ 

■°.2£ 

•3  & 

Macro- 

Micro- 

< 

12 

5  P. 

6  ° 

0Q 

sco  pical. 

scopical  . 
Pituitary 

61 

9    mos. 

Mar.  31 

Sections 

Died 

166  days 

None  until 

Nothing 

show 

Sept. 

last  48  hrs. 

abnormal 

normal 

small 

13 

of         life, 

piece  of 

when    fits 

brain 

occurred 

9 

Q1- 

Apr.  28 

Sections 
show 
small 
piece  of 
brain 

Killed 

Sept. 

27 

152     „ 

None 

Nothing 
abnormal 

Pituitary 
normal 

Total  extirpation  of   the  pituitary 

This  operation  (figs.  95  and  96)  was  effectually  performed 
on  six  animals.  In  all  cases  a  few  cells  of  the  reticulated  portion 
of  the  pars  intermedia  must  necessarily  be  left  at  the  base  of 
the  brain,  otherwise  the  third  ventricle  will  be  opened  and 
part  of  the  brain  removed. 

The  first  animal  died  shortly  after  the  completion  of  the 
operation — so  soon  that  it  is  possible  that  death  was  due  to  an 
overdose  of  ether  which  was  used  too  freely  during  the  experi- 
ment. Of  the  other  five  all  died  within  a  short  time — that  is 
to  say,  within  periods  ranging  between  22  and  36  hours.  In  all 
these  five  cases  the  animals  recovered  from  the  anaesthetic, 
and  were  able  to  take  nourishment  freely.     Before  long,  however. 


1  This  animal  and  bitch  no.  2  were  kept  side  by  side  in  the  animal  house.  Both 
died  with  convulsions  within  a  few  hours  of  one  another  man}-  months  after 
operation.  Strychnine  poisoning  was  suspected,  but  the  examination  of  the 
stomach  of  this  bitch  gave  a  negative  result.  No  lesions  were  found  in  the 
brains  of  these  animals  that  would  account  for  the  convulsions. 


142 


PHYSIOLOGY 


Fig.  94a. 
Bitch  9  before  control  operation.     (Photograph-) 


Fig.  94b. 
Bitch  9,  152  clays  after  control  operation.     (Pliotograjrft. 


REMOVAL   OF   THE    PITUITARY 


143 


Fig.  95. 

The  anterior  and  posterior  lobes  of  the  pituitary  removed  at  operation  from 
bitch  1.     (Photomicrograph.) 

X  15. 


<  « 


(:     I 


"-k; 


'  Sm 


Fig.  96. 

The  base  of  the  brain  a1  the  site  of  removal  of  the  pituitary  from  bitch  1. 
[Photomicrograph.) 


X  15. 


144 


PHYSIOLOGY 


Table  III. — Total,  or  Almost  Total,  Removal  of  the  Pituitary. 


23 


27 


30 


S   . 

•sa 

g  s 

3, 
p. 


7 
mos, 


7 
mos. 


3 

mos, 


29      3i 
mos. 


4 

mos, 


o.o 


9    |  Feb. 
mos.  I    J  7 


Apr. 
7 


Sept. 


Sept. 
30 


Nov. 
9 


Nov. 
10 


roscopical 
stigation  of 
es  removed 
operation. 

■6 
o 

'•3 

Eh 
O 

val  between 
ration  and 
death. 

■%  &  =>^- 

^  a  .2; 

M 

3  a 

5 

Sections 

Died 

Died  a 

show  total 

Feb. 

short 

anterior 

17 

while 

and    post- 

after 

erior  lobes 

opera- 
tion 

Sections 

Died 

24hrs. 

show  total 

Apr. 

anterior 

8 

and    post- 

erior lobes 

Sections 

Died 

22   „ 

show  total 

Sept. 

anterior 

9 

and   post- 

erior lobes 

Sections 

Died 

36    „ 

show  total 

Oct. 

anterior 

2 

and    post- 

erior lobes 

Sections 

Died 

36    „ 

show  total 

Nov. 

anterior 

11 

and    post- 

erior lobes 

Sections 

Died 

36    „ 

show  post- 

Nov. 

erior    lobe 

12 

only 

P.M.  findings. 


"3  3 

O  Q 


Macro- 
scopical. 


Did     not 
recover 
conscious- 
ness 


Dullness 
and      re- 
fusal    of 
food; 
finally 
coma. 
Respira- 
tions 10. 
Pulse  140 
Coma. 
Respira- 
tions 13 


Dullness ; 
then  coma 


Dullness 
and  re- 
fusal of 
food  ; 
finally 
coma 


Coma 


No  haemo- 
rrhage ; 
small 
blood-elut 
only 

Small 
blood-clot 
in       sella 
turcica 


Small 
blood-clot 
in  track 
of    opera- 
tion 
Small 
blood-clot 
in       sella 
turcica 


Small 
blood-clot 
in       sella 
turcica 


Small 
blood-clot 
in       sella 
turcica 


Micro- 
scopical. 


Stalk     with  ?  Anses- 
a  few   pars  thetic 
intermedia 
cells       at- 
tached 


Stalk     with 
a  few    pars 
intermedia 
cells     and 
blood-clot 
attached 


Removal 

of  pituit- 
ary 


Nothing  but  Removal 
small  blood-  of  pituit- 
clot  the  size  ary 
of  pituitary 


A   few  pars 
intermedia 
cells      with 
cysts  below 
3rd        ven- 
tricle,    and 
a       small 
blood-clot 
A    few    de- 
generated 
pars    inter- 
media cells 
lying         in 
blood-clot 
below     3rd 
ventricle 
A  few   pars 
intermedia 
cells    along 
base  of  brain. 
No  sign    of 
anterior    or 
posterior 
lobe 


Removal 
of  pituit- 
ary 


Removal 
of  pituit- 
ary 


Removal 
of  pituit- 
ary 


REMOVAL   OF   THE   PITUITARY 


145 


they  became  somnolent,  and,  although  it  was  sometimes  possible 
to  rouse  them  from  this  condition  and  to  get  them  to  stand  and 
take  food,  they  quickly  became  somnolent  again  as  soon  as  they 
were  left  alone.  After  a  few  hours  the  respirations  became  very 
slow  and  coma  set  in  ;  finally  death  supervened.  The  details 
of  these  operations  are  shown  in  table  III. 

No  observable  changes  occurred  in  the  genitalia  in  the  few- 
hours  of  life  subsequent  to  operation,  nor  were  any  definite 
changes  found  in  the  other  hormonopoietic  organs  in  these 
circumstances.  I  anticipated  finding  hyperplasia  in  the  thyroid, 
for  dishing  is  \  ery  definite  on  this  point,  but  in  no  case  was  any 
change  to  be  discovered. 

Partial  removal  of  the  pituitary 

Removal    of    the  Anterior    Lobe. — (a)  Total  removal  of  the 
pews  anterior. — In  only  two  experiments  was   the    anterior    lobe 


Fig.  97. 

Section  showing  large  portions  of  the  pars  anterior  removed  at  operation  from 
bitch  5.     {Photomicrograph.) 

X  15. 

almost    completely    removed   (table    IV).      It    seems    practically 
impossible  to  remove  the  entire   anterior  lobe  without   damaging 

10 


146 


PHYSIOLOGY 


the  posterior.  In  figure  97  are  shown  the  portions  of  the  pars 
anterior  removed  at  operation  from  bitch  no.  5. 

In  both  cases  death  followed  the  extensive  removal  of  the 
pars  anterior  within  a  few  hours. 

Nothing  abnormal  was  observed  in  the  other  hormonopoietic 
organs  after  operation. 


Table  IV. — Total  or  Almost  Total  Removal  of  the  Anterior  Lobe. 


05 

a> 

a  . 

■a  «» 

S  Ml 

o 

*■  a 
o  o 

n>'-g 

Microscopical 
investigation  of 
tissues  removed 

at  operation. 

■6 

eg 

■3 

O 

val  between 
'ration  and 
death. 

H  3 
o  o 

a  a 
3I 

P.M.  findings. 

•a 

rS 

Macro  - 

Micro- 

■s 

05 

o 

s 

-go 

CG 

scopical. 

scopical  . 

a 
■s 

5 

7 

Apr. 

Sections 

Died 

70  hrs. 

April      7, 

Nothing 

Blood-clot  in 

Removal 

mos. 

6 

show  total 

anterior 

lobe 

Apr. 
9 

none. 
April      8, 
none. 
April      9, 
extreme 
drowsi- 
ness ; 
finally 
coma 

abnormal 

and  around    of  ant- 
infundib-       erior 
ulum.      As    lobe 
far   as   can 
be  seen  the 
pars      ant-  1 
erior       has 
been        re- 
moved   en- 
tirely 

8 

5* 

Apr. 

Sections 

Died 

32    „ 

Dullness 

Nothing 

No  pars  ant    Removal 

mos. 

9 

show  two 

Apr. 

and       re- 

abnormal 

erior  to  be 

of  ant- 

large pieces 

11 

fusal      of 

found. 

erior 

of  anterior 

food ; 

Poor  section 

lobe 

lobe 

then  coma 

of  region 

The  genitalia,  too,  showed  no  changes  in  the  short  period  of 
time  that  elapsed  between  the  operation  and  the  death  of  the 
animals. 

(b)  Partial  removal  of  the  pars  anterior. — It  has  been 
mentioned  that  complete  removal  of  the  pars  anterior  alone 
is  practically  impossible,  and  that  the  removal  of  nearly  all  of 
it  is  usually  fatal.  Nevertheless,  it  is  quite  easy  safely  to 
remove  large  (figs.  98  and  100)  or  small  portions  of  the  anterior 
lobe  ;  consequently  observations  of  the  effects  produced  by  these 
operations  should  be  reliable. 

In  table  V  are  shown  the  results  of  removals  of  the  pars 
anterior.  There  were  five  experiments,  and  in  all  the  animals 
survived.  It  will  be  noticed  that  the  results  are  not  completely 
harmonious  in  regard  to  the  details. 


REMOVAL   OF   THE    PITUITARY 


147 


Table  V. — Partial  Removal  of  the  Anterior  Lobe. 


o 

3 
2  . 

Si  « 

ft 

o.o 
*a   - 

croscopical 
Bstigation  of 
ues  removed 
operation. 

-3 

a 
a>  2 

?! 

o  o 

a  3 

£>  o 

d 
© 

iS-d 

P.M.  findings. 

8           Z-2 
-d           |  «.§ 

Macro- 

Micro- 



«< 

■S-t= 

~           "3  a 

t-i 

«i 

«o 

£ 

scopical. 

scopical. 

grm. 

grm. 

3 

4 

Mar. 

Sections 

Killed  210  days 

March  11, 

6680 

5200 

Uterus, 

Partial      re- 

mos. 

10 

show  large 

Oct. 

none. 

ovaries  and 

moval        of 

portion  of 

6 

March  12, 

mammae 

pars    ant  - 

anterior 

drowsy. 

atrophied. 

erior 

lobe 

March  13, 

very 

Thyroid 
small 

drowsy. 

March  14, 

improved. 

Recovered 

13 

? 

May 

Sections 

Killed    60     „ 

Drank 

Uterus, 

Partial      re- 

4' 

show  fairly 

July 

some  milk 

ovaries  and 

moval        of 

large  piece 

3 

1        hour 

mammae 

pars  anterior 

of  anterior 

after 

slightly 

lobe 

operation. 
No  symp- 
toms. Re- 

atrophied 

covered 

15 

6 

June 

Sections 

Killed 

9    „ 

None.  Re- 

Nothing ab- 

Pituitary 

mos. 

2 

show  small 
portion  of 
anterior 
lobe 

June 
11 

covered 

normal. 
(Period  too 
short      be- 
tween ope- 
ration and 
death) 

much      dis- 
turbed. 
Much  hyper- 
plasia of  ex- 
isting    cells 
of    pars  an- 

terior  mixed 

with    blood - 

clot 

19 

G 

July 

Sections 

Killed 

108     „ 

Drank 

4850 

5350 

Nothing  ab- 

Most of  pars 

mos. 

5 

show  very 
large 

Oct. 

21 

some  milk 
1        hour 

normal  ; 
but  no 

anterior  re- 
moved. Pars 

amount  of 

after 

control    of 

posterior  in- 

anterior 

operation. 

genitalia 

tact 

lobe 

July  6, 

drowsy. 

July  7, 

drowsy. 

July  8, 

improved. 

Recovered 

taken  at  a 

previous 

operation 

24 

4 

Sept. 

Sections 

Killed 

10     .. 

Animal 

Uterus, 

Most  of  the 

mos. 

22 

show  very 

Nov. 

\  ery  weak 

ovaries  and 

pais  anterior 

large 

1 

through- 

mammae     removed. 

amount  of 

out  whole 

very 

Pars        pos- 

anterior 

period 

slightly 

terior        in- 

lobe 

atrophied. 

Thyroid 
very  large 

tact 

148  PHYSIOLOGY 

In  no  case  in  this  series  of  experiments  was  there  any  observ- 
able increase  in  weight.  Unfortunately  only  two  bitches  were 
weighed  before  as  well  as  after  operation,  and  of  these  no.  3 — 
shown  before  and  210  days  after  operation  in  figures  99a  and  99b 
— lost  weight  subsequently  to  operation  ;  the  other  (no.  19) 
increased  in  weight  in  accordance  with  its  normal  increase  in 
growth.  Some  of  the  animals  when  recovering  from  the  opera- 
tion showed  the  peculiar  condition  of  somnolence  already  de- 
scribed in  connexion  with  total  removal  of  the  pituitary.  As 
recovery  progressed  this  state  gradually  passed  off. 


Fig.  98. 

Section  showing  large  portion  of  pars  anterior  removed  from  bitch  3. 
(Photom  icrograph. ) 

X  15. 

Changes  in  the  hormonopoietic  organs  other  than  the  gonads 
were  not  found  except,  possibly,  in  the  case  of  the  thyroid 
from  bitch  no.  24.  In  this  animal  the  thyroid  was  observed 
macroscopically  to  be  considerably  enlarged,  but  on  histological 
examination  the  organ  was  found  to  be  normal. 

The  variability  in  the  results  would  not  be  difficult  to 
understand  if  it  were  only  in  the  case  of  the  removal  of  small 
portions  of  the  pars  anterior  that  no  symptoms  were  produced, 
while  excision  of  large  amounts  produced  changes  in  the  general 


REMOVAL   OF   THE    PITUITARY 


149 


Fig.  99a. 
Bitch  3,  before  operation.     (Photograph.) 


Fig.  99b. 

Bitch  3,  210  days  after  removal  of  a  large  portion  of  pars  anterior. 
(Photograph.) 


150 


PHYSIOLOGY 


condition  of  the  animal,  in  the  genitalia  and  in  the  other 
hormonopoietic  organs.  But  these  were  not  the  results  that 
were  obtained  ;  and  it  is  difficult  to  understand  why  the  removal 
of  large  portions  (fig.  100)  from  one  animal — no.  19 — should  give 
rise  to  no  ill  effects,  while  the  removal  of  smaller  pieces,  as  in 
some  of  the  other  animals,  should  cause  definite  changes  in  the 
genitalia. 

In  three  out  of  the  five  cases  in  which  portions  of  the  pars 
anterior  were  removed  the  uterus  (figs.  101a  and  101b)  and  ovaries 


Fig.   100. 

Section  showing  large  amount  of  pars  anterior  removed  from  bitch  19. 
{Photomicrograph. ) 


X  15. 


were  definitely  atrophied.  In  these  circumstances  we  find  in 
regard  to  the  uterus  that  there  is  first  of  all  atrophy  in  the 
muscular  coats,  and  that  this  is  soon  followed  by  atrophy  in  the 
endometrium.  The  changes  in  the  ovaries  will  be  described  later 
(p.  195). 

In  two  cases  nothing  abnormal  was  noted,  but  in  one  of 
these  the  length  of  time — nine  days — that  had  elapsed  between 
the  operation  and  the  post-mortem  examination  was  probably 
not  sufficient  to  permit  atrophic  changes  to  take  place  in  the 
genitalia.     In   the  remaining   case   no   control   was   taken   before 


REMOVAL   OF   THE    PITUITARY 


151 


Fig.  101a. 
Section  of  the  uterus  of  bitch  3  before  operation.      (Photomicrograph.) 


X40. 


T-V'':.r'->"  •    "'■■-.  -  ■•  v 


Fig    101b. 

Section  of  the  uterus  of  bitch  3,  210  days  after  partial  removal  of  pars  anterior. 

(Photomicrograph. ) 

X40. 


152 


PHYSIOLOGY 


. 


Fio.   102. 

Section  showing  posterior  lobe  removed  at  operation  from  bitch  16. 
{Photomicrograph. ) 


I 


X  15. 


*l 


.  V- 


'"'.'  •% 


Fig.  103. 

Section  showing  the  site  of  the  pituitary  after  removal  of  the  pars  posterior 
from  bitch  16.  It  will  be  seen  that  a  small  portion  of  the  pars  nervosa  at  the  neck 
was  left  behind.     (Photomicrograph.) 


X  15. 


REMOVAL    OF   THE   PITUITARY 


153 


the  operation  on  the  pituitary,  as  it  was  intended  that  a  fatal 
quantity  should  be  removed.  This,  however,  was  not  effected 
at  the  operation,  although  a  large  amount  was  excised  (fig.  100). 
The  uterus  and  ovaries  showed  no  change  from  the  normal  after 
an  interval  of  108  days.  Naturally,  in  any  case,  a  considerable 
lapse  of  time  must  occur  subsequently  to  the  operation  if 
definite  changes  in  the  genitalia  are  to  be  expected. 

Removal  of  the  Posterior  Lobe. — (a)  Total  removal  of  the 
pars  posterior. — In  only  one  case  was  total  removal  of  the 
posterior  lobe  effected  (figs.  102  and  103).  The  details  of  this 
case  are  shown  in  table  VI. 


Table  VI.- 

-Total  Removal  of 

THE 

Posterior  Lobe. 

"§ 

s 

■J  <o 

» 
ft 
< 

«  a 
0  0 

0 

Microscopical 
investigation  of 
tissue  removed 

at  operation. 

O 

■n 

<s> 

Killed 
Oct. 

00        Interval  between 
O-           operation  and 
4;                   death. 

"a  5 
.2  © 

m 

9 

a 
0 

£d 

P.M.  findings. 

Macro- 
scopical. 

Micro- 
scopical. 

16 

7 

111  OS. 

June 

1 

Sections 
show  total 

None 

grm. 
4700 

grm. 
5100 

Nothing       ab- 
normal.     The 

Shows     ab- 
sence of  the 

posterior 
lobe 

7 

uterus,    mam- 
mae,      and 
ovaries  had  de- 
veloped   since 
the  operation 

pars      pos- 
terior,   ex- 
cept       the 

neck 

The  animal  (no.  16) — shown  before  and  after  operation  in 
figures  101a  and  104b — had  no  symptoms  whatever.  There  was 
some  increase  in  weight,  but  only  in  accordance  with  the  growth 
of  the  animal.  The  uterus  (figs.  105,  A  and  b)  and  ovaries  (see 
fig.  132,  p.  198)  continued  to  develop,  and  no  changes  were 
observed   in  the  other   hormonopoictic  organs. 

(b)  Partial  removal  of  the  pars  posterior. — Ol  this  experiment, 
also,  there  was  only  one  case.  The  bitch  died  199  days  after 
operation  with  convulsions  (table  VII,  p.  156).  It  has  already 
been  suggested  that  the  animal  may  have  been  poisoned,  for 
this  and  a  control  animal,  mentioned  above,  both  died  within 
a  few  hours  of  one  another  with  the  same  symptoms. 

So  far  as  could  be  discovered  no  changes  in  the  genitalia  or 
elsewhere  had  been  caused  by  this  operation. 


154 


PHYSIOLOGY 


Fig.  104a. 
Bitch  16  before  operation.     {Photograph. 


Fig.  104b. 
Bitch  16,  128  days  after  removal  of  the  pars  posterior.     {Photograph.) 


REMOVAL   OF   THE   PITUITARY  155 


Fig.   105a. 

Section  of  the  uterus  of  bitch  16  before  operation 


. 


■ 


X60. 


Fig.   105b. 

Section  of  the  uterus,  which  has  developed,  of  bitch  16  128  days  after  total 
removal  of  the  pars  posterior. 

X  60. 


156 


PHYSIOLOGY 


Table  VII. — Partial  Removal  of  the  Posterior  Lobe. 


S  . 

'3  4; 

2  * 

o  o 
c-g 

«  ?! 

1=1  ft 

croscopical 
jstigation  of 
ue  removed 
operation. 

o 
a) 

rval  between 
^ration  and 
death. 

it 

CD    O 

si 

Ha 

a 

—      . 

£-d 

P.M.  findings. 

Macro  - 

Micro- 

<! 

M 

«i  ft 

l-H 

£° 

£ 

scopical. 

scopical. 

grm.      grm. 

2 

V 

Feb. 

Sections 

Died 

199  days 

None  until  !(J 

Nothing 

Dog  died   on 

mos. 

24 

show3mall 

Sept. 

iastlShrs. 

1  on 

abnormal 

a     Saturday 

amount  of 

II1 

of        life. 

Apr. 

night,      and 

posterior 

when  fits 

Ki 

had         been 

lobe 

occurred 

which  ul- 

dead some 
time     before 

timately 

post-mortem 

caused 

could          be 

death 

made.  Im- 
possible to 
cut  good  sec- 
tion   of    the 

parts 

Table  VIII. — Partial  Removal  of  the  Anterior  and  Posterior  Lobes. 


a) 
1« 

So 

pical 
ion  of 

moved 
tion. 

•6 

a 

SB 

M 
fg 

1 

>  _: 

P.M.  findings. 

n 

a&     llil 

.343 

c 

• 
'Q 

■°.2il 

'3"!*  » 
on 

1° 

zl. 

-t-    — 

'.so 

'5 

Macro- 
scopical . 

Micro- 
scopical. 

grm. 

grm. 

17 

6 

June  Sections  show 

Killed  172  days 

None. 

7350 

8550 

Rather 

Sections 

mos. 

25     almost    total 
posteriorlobe 
and   a    small 
amount       of 

Dec. 
14 

Animal 
came     on 
heat,  and 
had  coitus 

fat 

show  a  large 
amount    of 
anterior 
lobe        and 

anterior  lobe 

without 
becoming 

very     little 
posterior 

pregnant 

lobe 

25 

5 

Sept, 

Sections  show 

Killed 

61    „ 

None 

5000 

5500 

Nothing 

Poor  section 

mos. 

15 

almost    total 

Nov. 

(on 

ab- 

of region 

posterior 

5 

Oct.  1 

normal. 

lobe    with    a 

after 

medium 

oper- 

amount      of 

ation) 

anterior  lobe 

v 

1  See  footnote  on  p.  141. 


REMOVAL    OF    THE    PITUITARY  157 

Combined  Partial  Anterior  and  Posterior  Lobe  Removals. 
—In  both  the  cases  of  this  experiment  (table  VIII)  large  portions 
of  the  pars  posterior  and  small  amounts  of  the  pars  anterior 
(fig.  106)  were  removed.  In  neither  case  were  any  symptoms 
or  post-mortem  appearances  noted  which  could  be  ascribed  to 
the  operation.  Both  animals  put  on  weight,  bitch  no.  17 
becoming  rather  fat ;    this  animal,  moreover,  came  on  heat  and 


"  Fig.   106. 

Section  showing  portions  of  the  pars  posterior  (on  the  right)  and  a  small  portion 
of  the  pars  anterior  (on  the  left)  removed  from  bitch  17.     (Photomicrograph.) 

X  15. 


had  coitus,  but  did  not  become  pregnant.  The  genitalia  con- 
tinued to  develop,  and  no  changes  were  noted  in  the  hormono- 
poietic  organs. 

The  absence,  then,  of  specific  symptoms  following  the  simul- 
taneous removal  of  small  portions  of  the  pars  anterior  and  large 
amounts  of  the  pars  posterior  corresponds  with  the  state  of 
affairs  obtaining  after  similar  removals  separately  conducted  on 
different  animals. 


158  PHYSIOLOGY 


Compression  and  Separation  of  the  Stalk 

The  details  of  these  operations  are  shown  in  table  IX. 
The  results  which  they  produce  are  probably  identical,  although 
it  is  possible  that  absolute  severance  of  the  stalk  may  produce 
more  sudden  and  lasting  effects  than  compression. 

These  experiments,  as  I  shall  indicate  more  fully  when  dis- 
cussing the  results  obtained  by  others,  are  of  considerable  interest, 
for  in  all  three  cases  there  was  an  increase  in  weight  and  in  two 
(nos.  12  and  14)  the  condition  of  dystrophia  adiposogenitalis  was 
produced.     By  no  other  operation  was  I  able  to  obtain  this  result. 

In  figures  107a  and  107b  bitch  no.  14  is  shown  before  and  after 
operation,  and  in  figures  108a  and  108b  bitch  no.  12,  before  and 
after  operation.  In  the  second  case,  especially,  an  extreme 
condition  of  adiposity  is  to  be  seen  :  the  body-weight  of  this 
animal  increased  66  per  cent,  in  51  days.  In  figure  109  this 
bitch  is  shown  laid  open  at  the  post-mortem  examination. 

The  appearance  of  a  dog  with  dystrophia  adiposogenitalis 
is  remarkable,  and  no  photograph  does  justice  to  the  extra- 
ordinary degree  of  adiposity  which  may  occur.  In  general  ap- 
pearance the  animal  becomes  strikingly  seal-like  :  the  head  and 
limbs  look  too  small  for  the  body,  the  fur  becomes  erect  and 
the  breadth  of  the  back  causes  it  to  become  flattened  on  top. 
The  young  animal  remains  somatically  infantile. 

Both  of  the  animals  which  showed  considerable  increase  in 
weight  also  showed  complete  atrophy  of  the  uterus  (figs.  110a 
and  110b),  and  of  the  ovaries  and  mammae. 

Histological  examination  of  the  pituitary  region  shows  that 
at  the  line  of  separation  and  compression  there  is  a  formation 
of  new  fibrous  tissue,  and  that  the  cells  of  the  underlying  pars 
anterior  are  atrophied  and  widely  separated  (fig.   111). 

In  disposition  the  animal  is  lethargic  after  recovering  from  the 
postoperative  somnolence  which  is  pronounced:  it  sleeps  a  great  deal. 
Moreover,  when  standing  it  has  a  typical  appearance  :  the  tail  and 
ears  droop,  and  the  animal  appears  to  be  only  half-awake  (figs.  107b 
and  108b).  In  one  case  (no.  14)  the  thyroid  was  found  to  be  very 
large  indeed,  and  when  examined  histologically  the  vesicles  were 
seen  to  be  enormously  distended  with  colloid  (see  fig.  126,  p.  191). 


COMPRESSION  AND    SEPARATION    OF  THE   STALK     159 


Table  IX. — Compression  and  Separation  of  Stalk. 
Compression  of  the  stalk. 


4> 

71 

a  . 

CM    £ 

•  died 

5 

P.M. 

findings. 

5 

11 

— 

a 
< 

"3  5 

3 

s 

—  J3 "?                !=  5"            ^2 

r  g                        «              a  - 
%  z                                     ^ 

S3 

tg: 

Macro- 
scopical. 

Micro- 
scopical. 

grm. 

grm. 

li 

7 

May 

Killed 

L29  days  Drank         6000 

7100 

Large  amount 

Sections  show 

mos. 

18 

Sept. 

milk         1 

(on  July 

of  subcutan- 

whole pituitary, 

24 

hour  after 

28w.= 

eous  fat. 

but  cells  stain 

operation. 

7200) 

Uterus, 

badly,  are  separat- 

Fair 

ovaries  and 

ed      from     one 

amount  of 

mammae 

another  in  the 

adiposity, 

infantile. 

pars  anterior,  and 

i.e.  20   % 

Thyroid 

are  shrunken 

increase  in 

very  large 

(atrophied).      The 

weight   in 

stalk     is    severed 

71  days 

and    replaced    by 
new  fibrous  tissue. 
Thyroid      vesicles 
distended  with 
colloid 

Separation  of  the  stalk. 

121 

°2 

May 

Killed 

128  days 

For  first  3  3000 

5i  m i 

Uterus, 

Sections  show  line 

mos. 

19 

Sept. 

days     ex- 

(same 

ovaries  and 

of  cleavage  below 

24 

tremely 
drowsy  ; 
afterwards 
became 
abnorm- 
ally     fat. 
Increase  in 
weight, 
66    %    in 
51  days 

weight 
on  Jul. 
9) 

mammae 
intensely 
atrophied : 
very  large 
amount    of 
subcutaneous 
fat 

patch    of   normal 
pars  intermedia 
cells.     The  rest  of 
the  pituitary  is 
embedded  in 
fibrous  tissue 

21 

6£ 

Aug.  Killed 

80     „ 

Increased 

740(1 

8100 

Nothing     ab- 

Poor section ; 

mos. 

31      Nov. 
19 

in  weight 

normal, 

except  the 
mammae, 
which  are 

tissues  badly  fixed 

infantile 

1  This  specimen   (fig.    109)    is  now  in   the  Museum  of   the   Royal   College  of 
Surgeons,  England. 


160 


PHYSIOLOGY 


Fig.   107a. 
Bitch  14  before  operation.     (Pit olograph.) 


Fig.   107b. 
Bitch  14,  129  days  after  compression  of  the  infundibular  stalk.       {Photograph.) 


SEPARATION    OF   THE   STALK 


161 


Fig.    108a. 
Bitch  12  before  operation.     {Photograph.) 


Fig.   108b. 
Bitcli  12,  51  days  after  separation  of  the  infundibular  stalk.     (Photograph.) 

11 


162 


PHYSIOLOGY 


Fig.   109. 


Bitch  12  laid  open  at  the  post-mortem,  128  days  after  separation  of  the 
infundibular  stalk.  The  enormous  deposits  of  fat  can  be  well  seen,  also  the  two 
horns  of  the  atrophied  uterus.     {Photograph.) 


SEPARATION   OF   THE   STALK 


163 


Fig.   110a. 
Section  of  the  uterus  of  bitch  12  before  operation.     (Photomicrograph.) 


X  40. 


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h ::&- 


^pRi'" 


Fig.   110b. 

Section  of  the  uterus  of   bitch  12,  128  days  after  separation  of  the 
infundibular  stalk.     (Photomicrograph.) 


X  40. 


164  PHYSIOLOGY 

DISCUSSION    OF    RESULTS    OF    EXTIRPATION    OF    THE    PITUITARY 
AND     OF    SEPARATION    AND    COMPRESSION    OF    THE    STALK 

It  will  now  be  of  interest  to  see  how  far  the  foregoing 
experiments  confirm  or  contradict  the  work  of  others.  In  this 
connexion  it  will  be  sufficient  to  consider  the  pioneer  work  of 
Paulesco1,  and  the  subsequent  experiments  of  Cushing  and  his 
colleagues23  and  of  Biedl4  and  his  associates. 

The  work  of  Aschner5  is  less  reliable,  for  although  this 
investigator    was    able    to     produce     certain    of    the    abnormal 


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Fig.   111. 

l».      ft.    - 

Section  of  the  pais  anterior  of  bitch  14  after  compression  of  the  stalk.     The  cells 
are  atrophied,  and  new  fibrous  tissue  is  seen  above,  at  the  site  of  compression. 

X  200. 

phenomena  that  previously  had  been  recognized  by  others,  his 
methods,  which  have  been  justly  criticized  by  Biedl,  were  not 
exact,   since  he  used  the  oral  route.     Ascoli  and  Legnani6,  also, 

1  Paulesco,  N.  C,  V Hypophyse  du  cerveau,  Paris,  1908. 

2  Reford,  L.  L.,  and  H.  Cushing,  Bull.  Johns  HopL  Hosp.,  1909,  xx,  p.  105. 

3  Crowe,  S.  J.,  H.  Cushing,  and  J.  Homans,  Bull.  Johns  Hopk.  Hosp.,  1910, 
xxi,  127. 

4  Biedl,  A.,  Inner e  Sekretion,  2nd  ed.,  1913. 

5  Aschner,  B.,  Wien.  Klin.  Woch.,  1910,  xxxii,  572. 

6  Ascoli,  G.,  and  T.  Legnani,  Munch.  Med.  Woch.,  1912.  lix,  518. 


RESULTS    OF  OPERATIONS    ON  THE   PITUITARY     165 

so  far  as  I  can  gather,  do  not  appear  to  have  clearly  recognized 
that  different  lesions  produce  different  results. 

Paulesco's  work,  on  the  other  hand,  is  of  the  highest  merit, 
for  by  introducing  the  bitemporal  route  he  at  once  placed  the 
experimental  possibilities  on  a  sound  basis.  The  results  which 
he  obtained  may  be  summarized  as  follows  : — 

1.  Complete  extirpation   of  the   pituitary  caused  death  in   a 

short  time. 

2.  Partial  removal  of  the  pars  anterior  caused  no  symptoms 

other  than  adiposity. 

3.  Extensive  or  complete  destruction  (thermocautery)  of  the 

pars  anterior  resulted  in  death. 

4.  Removal  of  the  pars  posterior  caused  no  symptoms. 

5.  Separation    of    the    stalk    resulted    in    the    death    of    the 

animal. 

6.  Separation  of  the  pituitary  from  its  bed  in  the  sella  turcica 

produced  no  symptoms. 

Cushing  and  his  fellow-workers,  as  the  result  of  two  series 
of  careful  experiments,  in  which  they  adopted  with  slight 
improvements  the  technique  introduced  by  Paulesco,  obtained 
results  very  similar  to  his  ;  indeed,  the  only  differences  noted 
were  in  regard  to  partial  removal  of  the  pars  anterior  and  to 
separation  of  the  stalk. 

Cushing  and  his  colleagues  found  that  separation  of  the  stalk 
produced  the  same  effects  as  total  removal  with  immediate 
transplantation.  They  also  believed  that  the  adiposity  which 
occurred  in  their  animals  after  partial  removal  of  the  pars  anterior 
was  specific  ;  that  is  to  say,  while  Paulesco  had  observed  that  the 
animals  might  become  fat,  Cushing  and  his  associates  were  the 
first  to  recognize  the  importance  of  this  adiposity,  and  to  note 
that  it  was  identical  with  the  pathological  condition  previously 
known  as  dystrophia  adiposogenitalis,  since  there  was  also  genital 
atrophy.  Further,  these  investigators  found  that  in  young 
animals  persistent  infantilism  occurred  after  partial  removal  of 
the  pars  anterior1. 

Cushing  also  made  the  important  observation  that  the  sub- 
normal   temperature    always    found     with     dystrophia     adiposo- 

1  Aschner  also  claims  to  have  obtained  dystrophia  adiposogenitalis  by  partial 
removal  of  the  pituitary  by  the  oral  route.  There  appears  to  be  no  doubt,  how- 
ever, that  Cushing  made  the  first  communication  on  the  subject. 


166  PHYSIOLOGY 

genitalis  can  be  raised  by  injections  of  an  extract  made  from 
the  pars  anterior.  This  he  called  the  '  thermic  reaction  '.  On 
the  other  hand,  according  to  the  same  investigator1,  the  low 
blood-pressure  and  carbohydrate-tolerance  associated  with  this 
syndrome  are  relieved  by  injections  of  infundibulin. 

Again,  Cushing  and  his  fellow- workers  found  that  although 
total  extirpation  was  a  fatal  operation  the  effect  was  not  so  rapid 
in  young  as  in  older  dogs. 

Last,  Cushing  described  a  condition  of  '  cachexia  hypophyseo- 
priva '  which  was  considered  specific  of  deprivation  (complete 
or  almost  complete)  of  secretion  of  the  pars  anterior. 

Biedl2,  without  giving  details,  states  that  he  has  confirmed 
all  Cushing's  findings,  except  in  regard  to  stalk-separation,  which 
operation,  in  agreement  with  Paulesco,  he  found  to  cause  death. 
It  is  hardly  worth  while  to  dwell  on  Biedl's  results  in  the  absence 
of  details  other  than  those  given  in  his  book. 

Silbermark3,  in  the  reference  given  by  Biedl,  with  whom  he 
was  associated,  discusses  only  the  technique  of  the  operation. 
Apparently  the  results  he  obtained  with  Biedl  are  recorded, 
without  details,  only  in  Biedl's  work. 

My  experiments  have  not  entirely  confirmed  the  work  of 
Cushing  and  his  colleagues,  which  seems  to  be  the  most  satis- 
factory of  all  the  experimental  work  hitherto  carried  out  on 
the  subject.  It  will,  therefore,  be  of  interest  to  discuss  the 
points  of  confirmation  and  contradiction,  and  to  find,  if  possible, 
some  explanation  of  the  differences. 

The  results  of  my  experiments  concerning  the  effects  of  total 
extirpation  of  the  pituitary  and  of  the  removal  of  very  large 
portions  of  the  pars  anterior  confirm  the  statements  of  Paulesco 
and  Cushing  that  such  procedures  are  fatal. 

Sweet  and  Allen4  alone  of  recent  investigators  deny  that  the 
pituitary  is  essential  to  life  ;  but  undoubtedly  their  technique 
is  open  to  criticism. 

My  experiments  also  confirm  the  fact  demonstrated  by  Paul- 
esco and  Cushing  that  the  removal  of  the  pars  posterior  produces 
no  symptoms.     Further,  I  have  been  able  by  means  of  the  control 

1  Gushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Biedl,  A.,  Inner e  Selcretion,  2nd  ed.,  1913. 

3  Silbermark,  M.,  Wien.  Klin.  Woch.,  1910,  xxiii,  467. 

4  Sweet,  J.  E.,  and  A.  R.  Allen,  Ann.  Surg.,  1913,  lvii,  485. 


RESULTS    OF   OPERATIONS    ON   THE    PITUITARY     167 

specimens,  removed  before  the  operation  on  the  pituitary,  to 
show  that  the  genitalia  not  only  do  not  undergo  atrophy  but 
continue  to  develop  in  the  young  female  after  removal  of  this 
portion  of  the  pituitary. 

With  regard  to  the  points  wherein  my  experiments  gave 
results  different  from  those  obtained  by  Paulesco,  Gushing  and 
others,  undoubtedly  the  most  striking  is  in  connexion  with  the 
production  of  dystrophia  adiposogenitalis.  Whereas  Gushing — 
and  probably  Paulesco,  although  he  failed  to  recognize  the  im- 
portance of  the  condition — found  that  partial  removal  of  the 
pars  anterior  was  the  lesion  responsible  for  this  syndrome,  in 
none  of  the  cases  in  which  I  removed  portions  of  the  pars  an- 
terior did  dystrophia  adiposogenitalis  supervene,  although  when 
sufficient  was  removed,  and  there  was  a  considerable  lapse  of  time 
between  the  operation  and  death,  genital  atrophy  was  usually 
found.  In  one  case  there  was  an  actual  loss  of  weight  in  a  young 
animal  in  210  days.  This  animal  remained  stunted.  In  other 
cases  the  animals  increased  in  size. 

I  found,  however,  that  the  syndrome  dystrophia  adiposogenit- 
alis followed  compression  and  separation  of  the  infundibular 
stalk.  In  two  out  of  three  cases  there  was  atrophy  of  the 
genitalia  with  considerable  adiposity  :  in  one  case  the  increase 
amounted  to  66  per  cent,  of  the  body-weight  in  51  days. 

It  is  not  impossible  to  reconcile  these  diverse  conclusions, 
especially  if  we  study  the  difficulties  Cushing  encountered  when 
he  attempted  to  make  his  experimental  findings  conform  with 
his  clinical  observations.  Believing  that  reconciliation  was  not 
possible,  he  was  tempted  to  throw  over  his  experimental  results 
in  favour  of  the  clinical  evidence  that  was  in  conflict  with  them. 

It  will,  I  think,  be  sufficient  to  call  attention  to  the  chief  per- 
plexity with  which  Gushing  was  confronted.  As  we  have  seen, 
the  results  of  his  experimental  work  indicate  that  dystrophia 
adiposogenitalis  is  due  to  insufficiency  of  the  anterior  lobe.  But  in 
his  clinical  experience  Cushing  found,  as  already  mentioned,  that 
the  only  symptom  of  the  syndrome  dystrophia  adiposogenitalis 
relieved  by  the  extract  of  the  anterior  lobe  was  the  subnormal 
temperature.  While,  on  the  other  hand,  the  low  blood-pressure, 
and  the  carbohydrate-tolerance — and,  as  far  as  I  can  understand 
from  his  later  writings,  the  genital  dystrophy — were  mitigated  by 
the  extract  of  the  posterior  lobe.     In  view,  then,  of  these  clinical 


168  PHYSIOLOGY 

observations,  how  was  it  possible  to  attribute  this  syndrome  to 
the  experimental  removal  of  portions  of  the  pars  anterior,  as 
Cushing  himself  and  others  had  done  ?  Cushing  solved  the 
question  by  rejecting  his  experimental  conclusions. 

The  results  I  have  obtained  after  compression  and  separation 
of  the  stalk  appear  to  explain  the  paradoxes.  Such  an  opera- 
tion could  only  interfere  with  the  blood-supply  of  the  whole 
organ  ;  and,  if  infundibulin  do  pass  directly  into  the  third 
ventricle,  stop  this  source  of  supply. 

It  is,  however,  hardly  possible  that  the  pars  posterior  and 
its  secretion  have  anything  to  do  with  the  matter,  for  all  recent 
investigators  are  agreed  that  the  posterior  lobe  can  be  removed 
without  producing  any  symptoms.  Further,  since  I  found  it 
possible  to  remove  large  portions  of  the  pars  anterior  and 
the  entire  pars  posterior  without  causing  dystrophia  adiposo- 
genitalis,  but  was  able  to  produce  this  syndrome  by  compressing 
and  separating  the  stalk,  it  is  obvious  that  interference  with  the 
blood-supply  to  the  pituitary  produces  the  condition.  There 
seems  little  reason  to  doubt,  then,  that  this  syndrome  is  primarily 
produced  by  insufficiency  of  the  pars  anterior  ;  but  it  appears 
certain  that  the  only  sure  way  to  effect  this  is  to  interfere  with 
the  blood-supply.  If  this  be  done,  we  find  that  the  cells  of  the 
pars  anterior  become  shrunken,  atrophic  and  discrete  (fig.  Ill) — a 
state  of  affairs  which  is  always  found  in  the  human  subject  afflicted 
with  dystrophia  adiposogenitalis  (compare  fig.  161,  p.  247)  and  in 
the  hibernating  animal  during  the  winter-sleep  (fig.  65b,  p.  88). 

It  is  now  necessary  to  consider  how  the  foregoing  statements 
can  be  reconciled  with  the  facts  that  removal  of  the  posterior 
lobe  causes  no  symptoms,  yet  infundibulin  relieves  some  of  the 
symptoms — the  lowered  blood-pressure  and  the  carbohydrate- 
tolerance — in  dystrophia,  adiposogenital  is. 

I  have  long  held1  that  to  explain  these  facts  we  must  look 
upon  the  pituitary  as  one  organ  and  not  two.  Further,  from 
the  clinical  and  experimental  evidence  of  this  syndrome,  and  from 
other  evidence  which  has  been  discussed,  it  is  probable  that  the 
view  of  Herring2  concerning  the  determination  of  the  secretion 
of  the  pars  posterior  solely  and  directly  into  the  third  ventricle 
cannot  be   sustained,   and   that  this   secretion,   if  required,   can 

1  Bell,  W.  Blair,  Arris  and  Gale  Lectures  :  Lancet,  1913,  i,  819. 

2  Herring,  P.  T.;  Quart.  Joum.  Exper.  Physiol,  1908,  i,  121. 


RESULTS    OF   OPERATIONS    ON   THE   PITUITARY  169 

be,  and  is,  taken  up,  like  other  internal  secretions,  by  the  blood- 
stream. It  is  to  be  remembered  that  the  secretory  cells  of  the 
posterior  lobe — the  cells  of  the  pars  intermedia — are  derived  from 
the  same  source  as  those  of  the  pars  anterior  ;  consequently  while 
compression  and  separation  of  the  stalk  interrupt  the  blood- 
supply  to  all  these  cells,  the  ablation  of  the  pars  posterior  does 
not  remove  the  cells  of  the  pars  intermedia  situated  at  the  base 
of  the  brain,  nor  does  such  an  operation  interfere  with  the  pars 
anterior.  Hence  it  is  that  it  becomes  necessary  to  look  upon 
the  functions  of  the  pituitary  as  a  whole,  and  to  consider  this 
structure  as  one  organ  and  not  two.  The  fortuitous  juxtaposition 
of  the  epithelial  cells  and  the  pars  nervosa  has  probably  no 
relation  to  the  vital — essential  and  beneficial — functions  with 
which  the  pituitary  is  concerned.  Even  if  secretion  from  the  pars 
nervosa  do  pass  into  the  cerebrospinal  fluid  there  is  no  evidence  to 
show  that  this  is  essential,  beneficial,  or  even  the  normal  method 
by  which  infundibulin  is  taken  up  by  the  animal  economy. 

Special  attention  has  been  directed  by  dishing  to  the  peculiar 
somnolent  condition  in  which  the  animal  may  exist  for  some 
time  after  operations  which  decrease  the  jutuitary  secretion, 
especially  that  of  the  pars  anterior.  This  state,  which  has 
already  been  described,  is  quite  characteristic.  It  may  exist  in 
different  degrees  from  a  deeply  comatose  condition  to  merely 
mental  lethargy.  If  the  animal  becomes  really  comatose,  as  is 
the  case  after  complete  and  almost  complete  extirpation  of  the 
pituitary,  death  always,  in  my  experience,  supervenes.  But  some 
animals — for  example,  bitch  3  in  my  series — become  somnolent 
for  many  days  and  must  be  disturbed  and  lifted  out  of  their 
beds  in  order  to  get  them  to  take  food.  This  they  readily  do 
as  soon  as  they  are  sufficiently  aroused.  Animals  that  recover 
usually  pass  from  this  condition  into  one  of  mental  apathy, 
which  either  disappears  in  time  or  persists — according  to  the 
permanence  or  otherwise  of  the  diminished  secretion. 

There  is  little  further  to  be  said  at  present  concerning  the 
relation  of  experimental  pituitary  lesions  to  polyuria  and  gly- 
cosuria :  disturbance  of  the  pars  posterior  is  supposed  to  set 
free  glycogenolytic  and  diuretic  substances,  dishing  and  his 
colleagues  are  at  present  engaged  in  investigating  these  questions1, 
and  their  work  is  expected  to  modify  certain  existing  opinions. 
1  Gushing,  H.,  Private  Communication. 


170  PHYSIOLOGY 


EXTIRPATION    COMBINED    WITH    IMPLANTATION    OF    GRAFTS 

Crowe,  Cushing  and  Homans1  are,  so  far  as  I  know,  the  only 
operators  to  test  this  method  of  substitution-therapy.  These 
workers  were  able  to  prolong  the  life  of  dogs  in  which  the  total 
removal  had  been  performed,  but  not  to  save  them.  They  state 
that  the  graft  remained  viable  for  at  least  a  month.  Implanta- 
tion was  carried  out  in  some  cases  before  operation,  and  in  others 
after  extirpation. 

In  criticism  of  these  experiments  it  may  be  said  that  the 
conditions  for  successful  grafting  (see  p.  120  and  following)  were 
not  strictly  observed.  No  complete  account  is  given  by  these 
investigators  of  the  technique  which  they  employed.  What 
is  described  as  '  previous  '  implantation  might  have  been 
successful  if  a  portion  of  the  animal's  own  pituitary — especially 
of  the  pars  anterior — had  been  removed  at  the  time  the  graft 
was  made,  and  the  rest  of  the  organ  removed  subsequently. 
Again,  if  a  heteroplastic  graft  were  used  permanent  success  could 
not  be  expected.  Further,  the  site  usually  chosen  (cerebrum) 
by  these  workers  could  hardly  be  considered  vascular  enough  to 
ensure  successful  implantation. 

It  follows,  therefore,  that  these  experiments  cannot  be  con- 
sidered very  satisfactory  or  illuminating  ;  indeed,  it  is  highly 
probable  that  any  benefit  that  occurred  from  the  grafts,  as  Crowe, 
Cushing  and  Homans  themselves  admit,  was  due  to  the  absorp- 
tion of  the  secretion  contained  in  the  graft  at  the  time  of 
implantation. 


STIMULATION    OF    THE    PITUITARY    IN    SITU 

Stimulation  of  the  pituitary  has  been  practised  by  direct 
and  indirect  methods.  In  the  former  the  pituitary  has  been 
exposed — usually  through  the  basisphenoid — and  stimulated 
mechanically,  with  caustics  or  with  electric  currents.  This  is  a 
very  unreliable  method,  for  it  is  practically  impossible  to  limit 
the  stimulation  to  the  part  intended,  especially  when  electrical 
currents    are   used.     In   the    indirect   method  the   pituitary  has 

1  Crowe,  S.  J.,  H.  Cushing,  and  J.  Homans,  Bvll.  Johns  Hoph  Hosp.,  1910, 
xxi,  127. 


STIMULATION    OF   THE   PITUITARY  171 

been    excited    by  electric    stimulation    of    the   nerves    connected 
with  it,  or  by  hormones  injected  into  the  circulation. 

Direct  stimulation. — By  this  means  Cyon1  observed  con- 
siderable variations  in  the  blood-pressure,  and  in  the  cardiac 
rhythm ;  and  he  formulated  a  theory  which  assigned  to  the 
pituitary  body  the  function  of  regulating  the  intracranial  circula- 
tion. The  thyroid,  he  thought,  took  part  in  the  same  action. 
This  hypothesis  has  been  adversely  criticized  by  Biedl2  and 
others. 

Schafer3,  moreover,  found  that  injury  to  the  pituitary  in 
dogs  leads  to  marked  diuresis,  and  he  attributes  this  effect  and 
the  findings  of  Cyon — without  supporting  his  general  hypo- 
thesis— to  an  increase  in  the  secretion  which  is  brought  about 
by  stimulation. 

Masay4  confirmed  Cyon's  results,  but  Pirrone5  states  that 
stimulation  of  the  brain  in  the  neighbourhood  of  the  pituitary 
causes  vascular  disturbances  similar  to  those  produced  by 
stimulation  of  the  pituitary  itself. 

Weed,  Cushing  and  Jacobson6  found  that  faradization  of 
the  pituitary  causes  glycosuria. 

Stimulation  of  the  pituitary  by  placing  artificial  tumours 
in  the  neighbourhood  of  the  sella  turcica  is  a  method  which  I 
have  used  in  an  attempt  to  produce  the  symptoms  of  neigh- 
bourhood tumours. 

The  technique  I  adopted  was  to  expose  the  pituitary  by  the 
bitemporal  method  already  described,  and  after  exposure  to 
place  a  piece  of  specially  prepared  paste  in  the  neighbourhood 
of  the  pituitary  fossa.  The  paste  was  made  of  wax  heated  with 
barium  sulphate  to  make  a  sterile  mixture  opaque  to  X-rays, 
and  was  placed  in  position  while  soft. 

I  operated  in  this  way  on  three  animals  (table  X).  Two 
recovered  quickly  from  the  operation,  and  these  I  shall  discuss 

1  Cyon,  E.  v.,  Pfliiger's  Arch.,  1898,  Ixxii,  635. 

2  Biedl,  A.,  Innere  Sekretion,  2nd  ed.,  1913. 

3  Schafer,  E.  A.,  Proc.  Roy.  Soc.  Biol,  1909,  lxxxi,  Ser.  B,  442. 

4  Masay,  F.,  VHypophyse  These,  Bruxelles,  1908. 

5  Pirrone,  D.,  Rif.  Med.,  1903,  xix,  169  and  205. 

6  Weed,  L.  H.,  H.  Cushing,  and  C.  Jacobson,  Bull.  Johns  Hopk.  Hosp.,  1913, 
xxiv,  40. 


172 


PHYSIOLOGY 


directly.  The  third  bitch  was  evidently  in  so  much  pain,  when  it 
recovered  from  the  anaesthesia,  owing  to  pressure  of  a  very 
large  mass  of  paste,  that  it  was  destroyed  immediately. 


Table  X. — Imitation  Tumour  in  Sella  Turcica. 


aj 
cs 
O 

20 
22 
26 

+3 

CS 

a  . 

■ri  <v 

2* 
a 
p. 
< 

6 

mos. 

7 
mos. 

mos. 

o.2 

Q  p. 
o 

M 

o 

3 

Interval  between 

operation  and 

death. 

Clinical 
symptoms. 

CD  o 
<B  o 

a 

si 

P.M.  findings. 

Macro - 
scopical. 

Micro- 
scopical. 

July 
6' 

Sept. 

7 

Sept. 
29 

Killed 

Sept. 
27 

Killed 

Nov. 

3 

Killed 

Sept. 
29 

98  days 
57     „ 
1  hour 

Great  emacia- 
tion.    Glyco- 
suria 

Well       deve- 
loped       and 

fat.      Nearly 
20  %  increase 
in  57  days 

Seemed        in 
pain,         and 
therefore 
killed 

grm. 
8200 

grm. 
9800 

Large   tumour  at 
edge      of       sella 
turcica.     Uterus, 
ovaries  and  mam- 
mae atrophied 

Tumour  in  front 
of  pituitary. 
Nothing  ab- 
normal 

Large  tumour 
occupying 
sella  turcica 

Large   cyst    in 
pars  anterior 

The    lobes    are 
displaced       in 
their     relation 
to  one  another 

Of  the  other  two  dogs  the  first  showed  symptoms  soon  after 
operation.  It  became  listless,  and  progressively  and  quickly  lost 
weight,  in  spite  of  the  fact  that  it  was  able  to  eat  well  from 
the  first.  Eventually  the  animal  became  extremely  emaciated 
(fig.  112)  and  there  was  persistent  glycosuria ;  consequently, 
at  the  end  of  98  days,  it  was  killed. 

Figure  113  is  a  radiograph  of  the  tumour  in  situ,  taken  during 
life. 

The  animal  had  mange,  and  at  the  post-mortem  examination 
a  small  chronic  abscess  was  found  in  the  abdominal  wall  ;  but 
neither  of  these  lesions  could  have  been  responsible  for  the  general 
condition. 

The  tumour  was  found  to  be  encapsuled  and  overlying  the 
left  margin  of  the  sella  turcica.  The  pituitary  was  slightly  dis- 
placed, but  otherwise  was  normal  on  macroscopical  examination. 
An  histological  examination  showed  the  tumour  to  be  embedded 
in   the   overlying   brain -substance    and   encapsuled   with   fibrous 


STIMULATION   OF   THE   PITUITARY  173 

tissue.  The  pituitary  contained  a  large  cyst  in  the  anterior 
lobe  (fig.  114)  which  appeared  to  be  somewhat  compressed. 

The  second  of  the  two  bitches  which  lived  for  some  time 
after  the  operation,  had  a  large  artificial  tumour,  lying  slightly 
further  forward  (fig.  115)  than  that  in  the  case  just  described. 

This  animal  had  no  glycosuria,  and  it  increased  considerably 
in  weight  during  the  57  days  that  elapsed  between  the  operation 
and  the  date  on  which  it  was  killed. 

The  pituitary  was  found  to  be  remarkably  displaced,  the  pars 
posterior  being  completely  detached  from  the  pars  anterior. 


i& 


Fig.   112. 

Bitch  20,  98  days  after  operation,  showing  the  emaciation  and  attitude  of  weak- 
ness caused  by  glycosuria  due  to  the  pressure  on  the  pituitary  of  an  imitation 
tumour.      (Photograph. ) 

On  histological  examination  it  was  found  that  the  anterior 
lobe  was  more  or  less  in  the  normal  position,  but  that  the  pars 
posterior  was  tilted  out  of  the  basin  formed  for  its  reception  in 
the  pars  anterior  (fig.  116)  ;  consequently  a  section  through  the 
stalk  failed  to  show  the  pars  anterior.  In  this  case  the  displace- 
ment of  the  pituitary  appeared  to  be  indirect ;  that  is  to  say, 
the  floor  of  the  third  ventricle  was  displaced  to  the  opposite  side, 
and  there  was  no  actual  stimulation,  but  rather  interference  with 
the  stalk. 

Such  a  condition  would  account  for  the  increase  of  weight 
which  occurred  in  this  animal   after  operation.     In  the  human 


174 


PHYSIOLOGY 


Fig.  113. 


Radiograph,  taken  during  life,  showing  the  artificial  tumour  in  bitch  20.  It 
will  be  noted  that  the  zygoma  on  the  left  side  was  excised  as  usual  during  the 
operation.  (By  Thurston  Holland.) 


STIMULATION   OF   THE   PITUITARY 


175 


subject  it  is,  of  course,  well  known  that  tumours  in  the  neigh- 
bourhood of  the  pituitary  usually  lead  to  the  syndrome  dystrophia 
adiposogenitalis  by  causing  atrophic  changes  in  the  secretory 
cells. 

Paulesco1  has  published  a  paper  bearing  on  the  experimental 
aspect  of  this  subject,  but  I  have  been  unable  to  refer  to  it,  as 
it  is  at  present  unobtainable  in  this  country. 


Fig.   114. 

Section  of  the  pituitary  of  bitch  20,  98  days  after  operation,  showing  a  cyst  in 
the  pars  anterior  caused  by  an  imitation  tumour.      (Pliolomicrograph.) 

X  15. 

Indirect  stimulation.  —  As  already  mentioned,  Weed, 
Cushing  and  Jacobson2  have  shown  that  the  pituitary  may  be 
stimulated  through  the  main  trunk  of  sympathetic  nerve-fibres. 
These  investigators  came  to  the  following  conclusions  : — 

1.  Stimulation  of  the  superior  cervical  ganglion,  by 
faradization  or  even  by  the  manipulation  necessary  for  its 
exposure,  causes  glycosuria  in  the  rabbit,  cat  or  dog. 


1  Paulesco,  N.  C,  Ann.  de  Biol,  1911,  i,  221. 

2  Weed,  L.  H.,  H.  Cushing,  and  C.  Jacobson,  Bull.  Johns  Hopk.  Hosp.,  1913, 
xxiv,  40;   Amer.  Journ.  Physiol.  (Proc.  Amer.  Physiol  Soc).  1913.  xxxi,  xiii. 


176 


PHYSIOLOGY 


Fig.   115. 


Radiograph,  taken  during  life,  showing  the  artificial  tumours  in  bitch  22. 

(By  Thurston  Holland. 


STIMULATION   OF   THE   PITUITARY 


177 


2.  Stimulation  of  the  superior  cervical  ganglion  after 
exclusion  of  all  possible  downward  impulses  to  the  abdominal 
viscera  by  way  of  the  vagi,  cervical  sympathetic  trunks  or 
cervical  cord,  leads  to  glycosuria.  Further,  a  similar  result 
follows  separation  of  the  sympathetic  synapses  with  nicotine. 

3.  If  the  posterior  lobe  of  the  pituitary  be  previously 
removed  by  operation,  stimulation  of  the  cervical  sympath- 
etic fails  to  cause  glycosuria. 

These  experiments  support  the  view  that  the  pars  posterior 
secretes  a  glycogenolytic  substance. 


S 


[Fig.   116. 

Section  of  the  pituitary  from  dog  22,  57  clays  after  operation,  showing  the 
displacement  of  the  pars  anterior  and  pars  posterior  caused  by  an  imitation 
tumour.     (Photomicrograph. ) 

X  15. 


I  have  already  alluded  to  the  effect  an  extract  of  duodenal 
mucosa  is  said1  to  have  on  the  pituitary  secretion,  when  dis- 
cussing the  way  in  which  diuresis  is  caused  by  infundibulin. 

No  other  work  with  regard  to  the  effect  of  injections  of  horm- 
ones   on    the    pituitary  has    been    carried   out.     It  is  a  difficult 
field  of  research,  but  one  which  contains  interesting  possibilities. 
1  Cow,  D..  Journ.  Physiol,  1915,  xlix,  441. 

12 


THE    INTERRELATIONS    BETWEEN    THE    PITUITARY 
AND    THE    OTHER    HORMONOPOIETIC    ORGANS 

We  now  come  to  an  extremely  complicated  part  of  our  subject, 
and  one  which  yields  results  that  in  all  probability  are  fraught 
with  most  illuminating  meanings,  had  we  the  knowledge  necess- 
ary for  their  complete  interpretation. 

As  already  stated,  many  hypotheses  may  be  formed,  and 
many  deductions  drawn  from  the  experimental  results  obtained  ; 
but  there  are  many  loop-holes  for  the  escape  of  the  truth,  which 
seems  to  be  most  jealously  guarded  in  regard  to  the  correlations 
of  the  organs  of  internal  secretion. 

In  spite  of  the  isolated  positions  and  specific  functions 
assigned  to  these  organs,  there  can  be  no  doubt  in  the  mind  of 
any  one  who  carefully  considers  all  the  available  evidence  that 
the  hormonopoietic  glands  are  closely  connected  with  various 
physiological  systems,  such  as  the  vascular  and  genital  ;  and 
that  each  of  the  various  secretions  augments  or  counteracts  the 
others.  Normally,  then,  the  internal  secretions  are  well  co- 
ordinated ;  but  lesions  in  any  one  member  may  interfere  with 
the  smooth-working  effects  of  the  rest.  We  are,  however,  faced 
with  many  difficulties  when  we  seek  for  exact  information.  Thus, 
because  we  find  an  enlargement  and  apparently  an  increased 
activity  in  the  pars  anterior  and  pars  posterior  of  the  pituitary 
after  removal  of  the  thyroid,  are  we  to  suppose,  as  has  been 
done  by  Rogowitsch1,  Cyon2  and  others,  that  the  function 
of  these  parts  of  the  pituitary  is  supplementary  to  that  of  the 
thyroid  ?  If  so,  what  are  we  to  think  of  the  effect  of  ovarian 
removal  which  produces  very  similar  changes  in  the  pituitary 
body  ?  Does  the  secretion  of  the  pituitary  also  supplement 
that  of  the  genital  glands  ? 

1  Rogowitsch,  N.,  Zeigler's  Beitr.  z.  Pathol.  Anal.  u.  z.  Allg.  Pathol.,  1889,  iv,  453. 

2  Cyon,  E.  v.,  Pfliiger's  Arch.,  1898,  lxxii,  635. 


HORMONOPOIETIC    INTERRELATIONS  179 

It  is  usually  accepted  that  these  things  are  so,  but  there  is 
another  side  to  the  question.  Can  this  pituitary  activity  sub- 
sequent to  castration  and  thyroidectomy  be  an  expression  of 
an  increased  activity  due  to  the  removal  of  a  restraining 
influence  ? 

It  is  probable,  I  think,  that  both  effects  are  produced  at  the 
same  time.  First,  there  is  the  withdrawal  of  the  specific  ovarian 
secretion  from  the  blood,  and  a  deficit  occurs  in  the  organism  in 
regard  to  this  substance,  whether  its  action  be  that  of  a  hormone 
or  of  an  individually  active  secretion.  Second,  the  absence  or 
limitation  of  the  particular  secretion  may  remove  a  controlling 
factor,  as  evidenced  by  overaction  on  the  part  of  some  of  the 
remaining  members  of  the  hormonopoietic  system. 

It  is  possible  that  the  reason  why  physiologically  active  secre- 
tions of  various  organs,  such  as  the  ovary,  the  suprarenal  cortex 
and  the  anterior  lobe  of  the  pituitary,  have  not  been  obtained 
and  utilized  therapeutically  is  because  they  do  not  produce  their 
effects  single-handed  :  they  must  either  be  activated  by  or  com- 
bined with  some  other  substance,  as  they  are  normally  in  the 
body,  before  they  can  give  effect  to  any  properties  they  may 
possess.  We  have  direct  evidence  of  this  in  the  activity  of 
implantations  of  the  structures  mentioned,  as  opposed  to  the 
inactivity  of  their  extracts. 

In  view  of  what  has  been  said  above  regarding  the  impossib- 
ility of  deducing  anything  definite  from  the  facts  observed, 
until  we  have  the  further  information  concerning  pluriglandular 
effects,  we  shall  merely  describe  the  results  of  our  own  work  and 
that  of  other  observers  in  regard  to  connexion  between  the  other 
hormonopoietic  organs  and  the  pituitary,  without  attempting 
to  analyse  too  closely  the  complete  meaning  of  the  results 
obtained. 

Experimental  methods  of  investigation  consist  in  supplying 
a  surplus  of  one  or  more  internal  secretions,  or  in  putting  out  of 
action,  partly  or  wholly,  one  or  more  members  of  the  hormono- 
poietic system. 


180  PHYSIOLOGY 


SUPPLEMENTATION   WITH    PITUITARY  EXTRACTS 

There  is  no  reason  why  the  effects  of  excessive  doses  of  a 
prepared  extract  of  one  of  the  organs  of  internal  secretion 
should  not  produce  definite  effects  on  the  rest,  but  so  far  no 
investigations  appear  to  have  been  carried  out  on  these  lines, 
except  in  regard  to  supplementation  with  pituitary  extract. 

Renon  and  Delille1  performed  some  experiments  which,  they 
considered,  proved  that  repeated  injections  of  an  extract  of  the 
whole   pituitary  produce  hyperplasia  in  the  thyroid. 

In  my  own  experiments  on  guinea-pigs  I  injected  extracts 
made  from  the  anterior  and  posterior  lobes,  and  I  fed  animals 
on  extract  of  the  anterior  lobe. 

With  regard  to  the  experiments  carried  out  with  the  extract 
of  the  anterior  lobe,  the  only  definite  changes  noted  were  in  con- 
nexion with  the  anterior  lobe  of  the  pituitary,  which,  strangely 
enough,  showed  evidence  in  all  cases  of  abnormal  secretory 
activity.  In  the  animals  which  received  injections  daily  the  cells 
were  almost  entirely  chromophobe  and  were  arranged  in  a  well- 
marked  lobular  disposition  (fig.  117)  ;  while  feeding  with  the  same 
extract  produced  more  moderate  activity,  that  is,  profuse  eosino- 
philia  of  the  cells,  to  the  exclusion  of  the  other  varieties. 

In  the  thyroids  of  these  animals  the  colloid  was  always  plenti- 
ful and  the  vesicles  thin-walled  ;  but  it  is  difficult  to  interpret 
this  as  abnormal. 

In  the  suprarenal  cortex,  after  feeding  with  extract  of  the 
anterior  lobe,  there  appeared  to  be  considerable  vacuolation 
(fig.  118),  but  whether  this  was  due  to  the  ingestions  or  the 
lethal  anaesthetic,  it  is  not  easy  to  determine  ;  but  this  vacuola- 
tion did  not  occur  to  the  same  extent  in  other  experiments,  even 
when  the  animals  were  killed  with  chloroform. 

All  the  other  hormonopoietic  organs  appeared  normal  after 
injections  of,  and  feeding  with,  extract  of  the  pars  anterior. 

No  abnormal  appearances  whatever  were  noted  in  any  of 
the  organs  of  internal  secretion  after  injections  of  infundibulin. 

1  Renon,  L.,  and  A.  Delille,  Compt.  Rend.  Soc.  Biol,  1908,  lxv,  499. 


181 


Fig.   117. 

Section  of  the  pars  anterior  of  the  guinea-pig  showing  lobular  arrangement 
and  chromophobia  of  the  cells  after  repeated  injections  of  an  extract  of  the  pars 
anterior.     {Photomicrograph. ) 

X  150. 


Section  of  the  suprarenal  cortex  of  the  guinea-pig  after  repeated  inj 
an  extract  of  the  pars  anterior,  showing  vacuolation.     {Pholomicn 


FlQ.    IIS, 

tea-pig  after  repeated  injections  of 
ing  vacuolation.     {Photomicrograph.) 

X 


•  JO. 


182  PHYSIOLOGY 


REMOVAL  OF  THE  OTHER  HORMONOPOIETIC  ORGANS 

Much  more  work  has  been  done  in  regard  to  the  results 
that  follow  the  extirpation  of  various  hormonopoietic  organs. 
We  shall  consider  first  the  changes  found  in  the  pituitary 
body  after  removal  or  destruction  of  different  members  of  the 
internal  secretory  system ;  and,  in  the  second  place,  we  shall  briefly 
narrate  the  effects  produced  by  the  removal  of  the  pituitary 
body,  in  whole  or  part,  upon  these  same  organs — a  subject 
to  which  reference  has  already  been  made. 

The  effects  on  the  pituitary  body  of  removal  of  the 
thyroid  and  thyroparathyroid  apparatus 

Rogowitsch1  appears  to  have  been  the  first  definitely  to  trace 
some  close  connexion  between  the  pituitary  and  the  thyroid. 
Vincent2  believes  that  the  thyroid  and  parathyroids  are  closely 
related  in  regard  to  their  functions.  Most  physiologists,  however, 
look  upon  these  organs  as  being  independent  of  one  another. 

Finding  that  increased  activity  was  produced  in  the  pituitary 
by  thyroidectomy,  Rogowitsch  came  to  the  conclusion  that  the 
pituitary  body  acts  vicariously  for  the  thyroid. 

Other  observers  subsequently  confirmed  these  observations  ; 
and  more  recently  Herring3  conducted  a  series  of  experiments 
on  the  subject,  and  summarized  his  results.  No  changes  were 
found  by  him  in  the  anterior  lobe  ;  but  there  was  increased 
activity  in  the  cells  of  the  pars  intermedia,  especially  in  regard 
to  their  invasion  of  the  pars  nervosa  :  granular,  '  hyaline  ' 
or  '  colloid  '  bodies  were  observed  scattered  throughout  this 
portion  of  the  pituitary,  and  collected  together  at  the  neck  and 
beneath  the  floor  of  the  third  ventricle. 

This  investigator  concluded,  therefore,  that  these  '  hyaline  ' 
bodies,  as  he  called  them,  find  their  way  into  the  third  ventricle. 
Further,  Herring  noted  a  change  in  the  ependymal  cells  lining 
the  infundibular  recess  and  third  ventricle  in  the  rabbit,  and  he 
observed,  also,  that  they  secreted  and  liberated  "  small,  clear, 
globular  bodies  ".     The  neuroglia,  too,  he  states,  was  proliferated. 

1  Rogowitsch,  N.,  Zeigler's  Beitr.  z.  Pathol.  Anat.  u.  z.  Allg.  Pathol,  1889,  iv,  453. 

2  Vincent,  Swale,  The  Internal  Secretions,  Lond.,  1912. 

3  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol.,  1908,  i,  281. 


EFFECTS   ON   PITUITARY    OF   THYROIDECTOMY     183 

Degener  and  Livingston1  have  observed  that  removal  of  the 
thyroparathyroid  apparatus  in  rabbits  is  followed  by  a  con- 
siderable increase  in  the  weight  of  the  pituitary.  After  some 
months  it  was  found  that  the  average  weight  of  the  pituitaries 
in  milligrammes  per  kilogramme  of  the  body- weight  was  11*4 
for  the  control  animals,  and  17*6  for  the  animals  previously 
subjected  to  the  operation. 

My  own  observations2  were  carried  out  on  cats,  several  of 
which,  owing  to  incomplete  parathyroidectomy,  survived  for  some 
time.  Some  of  the  animals  were  pregnant  when  the  thyroid 
was  removed,  and  some  non-pregnant.  As  the  results  obtained 
appear  to  be  constant  in  certain  respects  under  similar  conditions 
so  far  as  the  pituitary  is  concerned,  I  shall  give  the  protocols 
of  a  few  of  the  experiments.  The  extent  of  the  changes  vary, 
of  course,  with  the  length  of  time  that  has  been  allowed  to 
elapse  between  the  extirpation  experiment  and  the  death  of  the 
animal.  In  those  animals  which  lived  for  some  time  no  doubt 
some  parathyroid  tissue  was  left  behind  :  but  in  all  definite 
thyroid  insufficiency  was  produced.  Pregnancy,  too,  seemed  to 
accentuate  the  effects  on  the  pituitary  of  thyroidectomy. 

Experiment  I. — Thyroid  removal :  Cat,  pregnant  about 
full-term. 

October  4th.     Thyroid  apparatus  removed. 
October  6th.     Animal  died,  with  convulsions. 
Interval  between  the  operation  and  death  :   48  hours. 
Histological  examination  of  the  pituitary  : 
Anterior  lobe.     Very  few  large  chromophobe  '  pregnancy 
cells  '  to  be  seen  :  practically  all  the  cells  are  eosinophil. 

Pars  intermedia.  There  is  much  colloid  secretion  in 
the  reticulated  groups  of  cells  beneath  the  third  ventricle. 
The  cells  of  the  pars  intermedia  lining  the  cleft  are  fused, 
and  the  appearance  presented  is  as  though  the  nuclei  of 
the  cells  are  lying  in  a  mass  of  granular  secretion 
(fig.    119). 

Pars  nervosa.  This  is  compact,  and  is  studded  with 
granular  bodies  ;  most  have  nuclei,  but  in  some  the  nuclei 
have  disappeared  (fig.  120). 

1  Degener,  L.  M.,  and  A.  E.  Livingston^  Amer.  Journ.  Physiol.  (Proc.  Amer. 
Physiol.  Soc),  1913,  xxxi,  xxiv. 

2  Bell,  W.  Blair,  Arris  and  Gale  Lectures  :  Lancet,  1913,  i,  707. 


184 


PHYSIOLOGY 


»  9 


I 

Fig.   119. 

Section  of  the  pars  intermedia  of  the  pregnant  cat  48  hours  after  thyro- 
parathyroidectomy,  showing  secretory  activity.     (Photomicrograph.) 


X  250. 


*  * 


* 


#  M* 


$# 


■r 


Fig.   120. 

Section  of  the  pars  nervosa  of  the  pregnant  cat  48  hours  after  thyroparathyroid- 
ectomy,  showing  invasion  of  the  pars  nervosa  by  the  cells  of  the  pars  intermedia. 
(Photomicrograph. ) 

X  500. 


EFFECTS    ON    PITUITARY   OF   THYROIDECTOMY     185 

Experiment  II. — Thyroid  removal :  Cat,  pregnant  nearly 
full-term. 

October  20th.     Thyroid  apparatus  removed. 

October  23rd.  Three  kittens  born  alive.  All  were 
suckled. 

November  12th.     The  last  of  the  kittens  died. 

November  20th.     Animal  died. 

Interval  between  the  operation  and  death  :  30  days. 


Vo1 


** 


JH* 


Fig.   121. 

Section  of  the  pars  anterior  of  puerperal  cat  30  days  after  thyroidectomy  during 
pregnancy,  showing  large  chromophobe  cells.     (Photomicrogra])h.) 

X  500. 


Histological  examination  of  the  pituitary: 

Anterior  lobe.  The  middle  portion  contains  many  large 
chromophobe  '  pregnancy  cells  '.  There  is  no  marked 
eosinophilia  except  among  the  cells  forming  the  upper  and 
lower  limits.  Some  empty  spaces  arc  to  be  seen.  Under 
a  higher  magnification  much  secretion  can  be  detected  round 
the  'pregnancy  cells',  giving  the  appearance  of  syncytium. 
A  few  large  basophil  cells  can  also  be  observed  (fig.  121). 

Pars  intermedia.  The  outlines  of  the  cells  are  blurred  ; 
there  is  '  vacuolation ',  and  great  secretory  activity  (fig.  122). 


186 


PHYSIOLOGY 


X 


•     9 


Fig.   122. 

Section  of  the  pars  intermedia  of  the  puerperal  cat  30  clays  after  thyroidectomy 
during  pregnancy,  showing  '  vacuolation '  and  secretory  activity.  {Photomicro- 
graph.) 

X400. 


Section  of  pars  anterior  of  the  cat  130  days  after  thyroidectomy  during  pregnancy, 
showing  'vacuolation'  due  to  excessive  secretion.     (Photomicrograph.) 

X  60. 


[Facing  page  18b. 


PLATE    3. 


Section  of  the  pars  anterior  of  the  cat  130  days  after  thyroid- 
ectomy during  pregnancy.  There  is  continence  of  chromophobe  cells 
and  '  vacuolation' — probably  due  to  accumulations  of  secretion  only  a 
few  scattered    eosinophil  cells  are  to  be  >een. 

X  500 

(Direct  colour  photomicrograph). 


Faring  page  187.] 


PLATE    4. 


Section  of  the  pars  anterior  of  the  non-pregnant  cat  79  days  after 
thyroidectomy,  showing  many  large  chromophobe  cells  lying  among 
strongly  staining  eosinophils. 

X  500 
(Direct  colour  photomicrograph  >. 


EFFECTS   ON   PITUITARY   OF   THYROIDECTOMY     187 

Pars  nervosa.  Hyaline  or  granular  bodies  are  not  dis- 
cernible ;  but  the  pars  nervosa  seems  to  be  invaded  by  cells 
from  the  pars  intermedia  ;  and  at  the  neck  the  secretion 
of  the  cells  is  collected  as  if  about  to  be  passed  into  the 
nervous  portion. 

Experiment  III. — Thyroid  removal :  Cat,  pregnant  about 
20  days. 

June  19th.     Thyroid  removed. 

June  29th.     Two  premature  kittens  born. 

October  24th.     Animal  killed  with  chloroform. 

Interval  between  operation  and  death  :   130  days. 

Histological  examination  of  the  pituitary : 

Anterior  lobe.  Under  a  low  magnification  the  anterior 
lobe  appears  to  be  extensively  vacuolated  (fig.  123).  The 
cells  are  chiefly  chromophobe  (plate  3),  but  there  are  a  few 
scattered  eosinophils.  The  condition  of  '  vacuolation '  is  seen 
to  be  due  to  excessive  secretion,  in  some  places  in  the  cells, 
and  in  others  between  the  cells ;  and  in  the  latter  case  the 
secretion  is  often  surrounded  by  a  vesicular  arrangement  of 
the  neighbouring  cells. 

The  cells  of  the  pars  intermedia  are  well  defined  and  not 
much  fused. 

Pars  nervosa  seems  to  be  teased  out,  but  there  is  no 
unusual  invasion  by  pars  intermedia  cells. 

Experiment  IV. — Thyroid  removal :    Cat,  non-pregnant. 

June   12th.     Thyroid  removed. 

August  30th.     Animal  killed  with  chloroform. 

Interval  between  operation  and  death  :   79  days. 

Histological  examination  of  the  pituitary : 

Anterior  lobe.  This  is  largely  composed  of  eosinophil 
cells ;  but  there  are  many  active  chromophobe  cells  to  be 
seen  (plate  4). 

Pars  intermedia.  There  is  considerable  activity  in  the 
cells  of  the  pars  intermedia,  and  faintly  staining  basophil 
(neutrophil)  secretion  can  be  seen  in  the  cleft  (fig.   124). 

Pars  nervosa.  This  portion  of  the  pituitary  is  finely 
reticulated,  but  there  is  no  invasion  by  cells  of  the  pars 
intermedia. 

It    appears,    therefore,  that,   while    there    is    undoubtedly    an 


188  PHYSIOLOGY 

increase  in  the  activity  of  the  pituitary  body  after  thyroidectomy, 
the  changes  observed  are  greater  in  the  pituitary  of  the  pregnant 
animal  than  in  that  of  the  non-pregnant.  Further,  while  the 
changes  observed,  if  correctly  interpreted,  all  indicate  an  increase 
of  activity  after  thyroidectomy,  the  appearances  vary  according 
to  the  extent  of  thyroparathyroid  insufficiency,  as  indicated  by 
the  immediate  effect  on  the  animal,  by  the  length  of  time 
between  the  operation  and  death,  and  probably  also  according 
to  the  period  of  pregnancy. 


•   I 


"*\ 


v 
is- 


FlG.    124. 

Section  of  the  pars  intermedia  of  the  non-pregnant  cat  79  days  after 
thyroidectomy,  showing  secretion  in  the  cleft.      (Photomicrograph.) 

X500. 

The  alterations  in  the  pituitary  as  the  result  of  thyroidectomy, 
as  I  have  observed  them,  may  be  summarized  as  follows  :  — 

Anterior  lobe.  Contrary  to  the  opinion  expressed  by  Herring 
who  operated  upon  (?  non-pregnant)  dogs,  cats  and  rabbits,  I 
believe  that  definite  changes  do  occur  in  the  anterior  lobe.  These 
changes  appear  to  vary  from  an  increased  eosinophilia  of  the 
cells,  with  scarcity  of  basophil  cells  and  the  presence  of  numerous 
neutrophil  cells  (plate  4),  to  a  condition  of  great  activity  when 
the  thyroid  is  removed  during  pregnancy,  and  the  animal  survives 
for  a  long  period   (plate   3).       In  the  last-named  circumstances 


EFFECTS   ON   PITUITARY    OF   THYROIDECTOMY     189 

the  cells  of  the  anterior  lobe  become  filled  with  secretion  which 
may  give  rise  to  an  appearance  of  vacuolation  ;  and  they  are, 
also,  large  and  for  the  most  part  chromophobe. 

Pars  intermedia.  We  find  that  there  is  considerable  activity 
in  the  cells  which  line  the  cleft  and  in  the  reticulated  groups  at 
the  base  of  the  third  ventricle.  The  cells  in  the  reticulated 
portion  appear  always  to  remain  discrete,  and  to  produce  neutro- 
phil secretion,  as  in  normal  circumstances  ;  while  the  cells  of 
the  pars  intermedia  lining  the  cleft  secrete  faintly  staining 
granular  material  either  into  the  cleft  (fig.  124),  or  on  the  surface 
of  the  pars  nervosa.  In  conditions  of  great  activity  the  cells 
themselves  always  seem  to  fuse  (figs.  119  and  122)— the  nuclei 
appearing  to  lie  among  a  mass  of  secretion. 

The  pars  nervosa  may  contain  much  granular  secretion  in 
degenerating  cells,  or  free. 

I  have  been  unable  to  confirm  Herring's  observations  as  to 
the  increased  activity  of  the  ependymal  and  neuroglial  elements. 

Noav,  it  will  have  been  noticed  that  while  the  appearances 
described  above  all  indicate  a  condition  of  increased  activity, 
exactly  the  same  appearances  are  not  seen  in  all  the  instances 
described  and  illustrated  ;  but,  as  I  have  already  pointed  out, 
I  have  selected  examples  in  which  the  circumstances  as  to  rela- 
tive insufficiency,  length  of  life  and  so  on,  varied.  I  would, 
however,  emphasize  the  fact  that  I  have  found  with  similar 
conditions  and  in  similar  circumstances  practically  the  same 
appearances  always  produced. 

The  interpretation  of  my  results  does  not  appear  to  be  very 
difficult ;  and  I  hope  in  the  explanation  to  throw  some  light  on 
that  least  understood  of  all  the  problems  in  connexion  with  the 
pituitary — the  relation  of  the  anterior  lobe  to  the  pars  inter- 
media and  the  pars  nervosa. 

It  will  have  been  noted  that  in  no  ease  were  all  three  parts 
of  the  pituitary  found  in  a  state  of  excessive  activity  at  the  same 
time.  In  experiment  II  we  have  the  nearest  approach  to  this, 
and  in  this  animal  no  granular  or  other  secretion-masses  are 
to  be  seen  in  the  pars  nervosa.  In  experiment  III  the  activity 
of  the  anterior  lobe  is  most  marked  ;  while  the  cells  of  the  pars 
intermedia  are  not  very  active,  nor  is  there  secretion  in  the  pars 
nervosa.  In  experiment  I,  in  which  there  was  acute  thyroid 
(including  parathyroid)  insufficiency,  as  indicated  by  death  with 


190  PHYSIOLOGY 

convulsions  in  48  hours,  there  was  considerable  activity  in  the 
pars  intermedia  and  pars  nervosa,  without  excessive  activity  in 
the  pars  anterior. 

These  facts  all  seem  to  point  to  the  conclusion  that  the  pituit- 
ary body  is  one  organ  ;  and  that  the  functional  activity  of  the 
posterior  lobe  is  dependent  on  the  functional  activity  of  the 
anterior.  Further,  it  appears  that  the  action  is  not  necessarily 
continuous  in  every  portion  at  the  same  time — indeed,  the  reverse 
appears  to  be  more  common.  Later,  I  shall  adduce  patho- 
logical evidence  in  support  of  this  hypothesis — showing  that 
the  function  of  each  portion  is  dependent  on  the  integrity  of  the 
whole. 

Effects  on  the  thyroid  of  partial  and  complete  removal   of 

the  pituitary 

Owing  to  the  fact  that  the  number  of  operators  who  have 
successfully  excised  the  pituitaries  of  animals  is  very  small, 
observations  concerning  the  effects  of  removal  of  the  pituitary 
upon  the  thyroid  are  limited.  Allusion  has  already  been  made 
to  this  question  in  connexion  with  experimental  operations  on 
the  pituitary,  but  for  the  sake  of  completeness  the  observations 
recorded  may  be  briefly  enumerated  here. 

Crowe,  Cushing  and  Homans1  observed  a  hyperplasia  in  the 
first  forty-eight  hours  after  complete  removal ;  and,  if  the  animal 
survived  the  complete  or  nearly  complete  extirpation  of  the 
pituitary,  a  '  functional  involution  '  of  the  thyroid,  with  accumu- 
lation of  colloid  in  the  vesicles  was  noted. 

I  was  unable  in  my  experiments  to  detect  the  hyperplasia 
mentioned  by  Cushing.  When  any  abnormality  was  noted  in 
the  thyroid  it  was  of  the  nature  of  excessive  accumulation  of 
colloid. 

In  figure  125  is  seen  the  thyroid — apparently  normal,  or  with 
only  slight  excess  of  colloid — 70  hours  after  complete  removal 
of  the  pars  anterior  of  the  pituitary.  According  to  Cushing 
there  should  have  been  hyperplasia. 

Figure  126  shows  the  excess  of  colloid  found  in  a  case  of 
dystrophia  adiposogenitalis  129  days  after  the  compression  of  the 

1  Crowe,  S.  J.,  H.  Cushing,  and  J.  Hoinans,  Bull.  Johns    Hopk.  Hosp.,  1910, 
xxi,  127. 


EFFECTS    ON  THYROID    OF    PITUITARY  REMOVAL    191 


k:;.. 


M. 


y~\ 


"VW-.   »      ,- 


"Ysr-1 


V~ 


r.--  —-i 


■ 


-*- 


-« 

w 


«£J 


/-■a  "N 


• 


, 


- 


Fig.   125. 


Section  of  the  thyroid  of  the  bitch  70  hours  after  total  extirpation  of  the 
pars  ancerior.     There  is  no  departure  from  the  normal. 


&r 


X60. 


- 


&~^-. 


■ 


" 


Fig.   126. 

Section  of  the  thyroid  of  the  bitch  129  days  after  compression  of  the  stalk  of 

the  pituitary.     There  is  an  abnormal  amount  of  colloid  in  the  vesicles. 

X  60. 


192  PHYSIOLOGY 

infundibular    stalk.      In  this  case  the  size  of  the    thyroid  was 
observed  to  be  twice  that  of  the  normal  organ. 

Neither  removal  of  the  whole  pituitary  nor  of  the  posterior 
lobe  produces  any  change  in  the  thyroid  that  can  definitely 
be  pronounced  to  be  abnormal. 


Effects  on  the  pituitary  of  removal  of  the  ovaries 

That  there  is  a  close  interrelation  between  these  two  members 
of  the  internal  secretory  system  has  long  been  known,  and  many 
interesting  hypotheses  have  been  formed. 

Mayer1  and  others  believe  that  the  pituitary  is  able  to  act 
vicariously  for  the  ovaries,  since  it  enlarges  in  pregnancy  and 
after  castration.  It  has  even  been  suggested  that  the  enlarge- 
ment of  the  hands  and  lips  sometimes  observed  in  pregnancy 
is  due  to  excessive  pituitary  secretion  following  ovarian  in- 
sufficiency. So,  too,  hcmianopia,  which  on  rare  occasions  is 
seen  in  pregnancy,  has  been  attributed  to  the  pressure  of  the 
enlarging  pituitary  on  the  optic  tract.  As  we  have  already  noted, 
the  hyperplasia  that  occurs  during  gestation  is  chiefly  due  to 
large  chromophobe  cells  of  the  anterior  lobe. 

Degener  and  Livingston2  have  not  found  any  increase  in  the 
weight  of  the  pituitary  after  castration. 

I  have  castrated  many  female  cats,  and  many  months  sub- 
sequently have  examined  the  pituitary  bodies.  Examples  of 
the  typical  effects  on  the  pituitary  are  shown  in  the  following 
protocols  : — • 

Experiment  I. — Ovarian  removal :    Cat,  non-pregnant. 
February  21st.     Ovaries  removed. 
October  23rd.     Animal  killed  with  chloroform. 
Interval  between  operation  and  death  :   245  days. 
Histological  examination  of  the  pituitary  body  : 
Anterior   lobe.     There   is   a   very  large  preponderance    of 
eosinophil  cells  ;    so    much    so    that    most    fields    examined 
show  only  eosinophils  (plate  5). 

Pars    intermedia.      The    cells    appear   fused.     There   are 

1  Mayer,  E.,  Arch.f.  Gyn,,  1910,  xc,  600. 

2  Degener,  L.  M.,  and  A.  E.  Livingston,  Amer.  Journ.  Physiol.  (Proc.  Amer. 
Physiol.  Soc  ),  1913,  xxxi,  xxiv. 


[Facing  page  192. 


PLATE    5. 


Section   of   the  pars  anterior  of  the   non-pregnant  cat    245  days 
alter  oophorectomy,  showing  intense  eosinophilia  of  the  cells. 


X  500 


(Direct  colour  photomicrograph). 


Facing  page  193.] 


EH 


PLATE    6. 


Section  of  the  pars  intermedia  of  the  non-pregnant  cat  245  days 
after  oophorectomy,  showing  eosinophil  colloid. 

X  500 

(Direct  colour  photomicrograph). 


EFFECTS    ON    PITUITARY   OF   OOPHORECTOMY     193 


colloid-vesicles,  and  in  one  place  a  colloid-cyst.  The  colloidal 
material  is  eosinophil  (plate  6). 

Pars  nervosa.  This  structure  has  a  teased-out  appear- 
ance.    There  are  no  granular  or  '  hyaline  '   bodies. 

Experiment  II.— Ovarian  removal :   Cat,   non-pregnant. 

April  24th.     Ovaries  removed. 

November  20th.     Animal  killed  with  chloroform. 

Interval  between  operation  and  death  :   210  days. 


*      m^ 


a 


Iv 


•  *■ 

9 


i 


% 


Fig.  127. 

Section  of  the  pars  anterior  of  the  non-pregnant  cat  210  days  after 
oophorectomy  showing  eosinophils,  large  chromophobe  cells  with  clear  nuclei,  and 
a  few  basophils.      {Photomicrograph.) 

X  500. 

Histological  examination  of  the  pituitary  body  : 

Anterior  lobe.  This  is  largely  composed  of  eosinophil 
cells  ;  but  there  are  many  active  chromophobe  cells,  and  at 
the  periphery  some  faint,  and  a  few  dark,  basophil  cells 
(fig.  127). 

Pars  intermedia.  There  is  considerable  degree  of  fusing 
of  the  cells  ;  and  there  is  much  eosinophil  secretion, 
especially  in  the  reticulated  portion  (fig.  128). 

In  the  compact  portion  at  the  neck  are  to  be  seen 
coarsely   granular    cells,   exactly    resembling    the    nucleated 

13 


194 


PHYSIOLOGY 


<*       l 


% 


Fig.   128. 

Section  of  the  reticulated  part  of  the  pars  intermedia  in  the  non-pregnant 
cat  210  days  after  oophorectomy,  showing  eosinophil  secretion. 


| 


« 


%'  t 


mU 


X500. 


Fig.   129. 

Section  of  the  pars  posterior  of  the  non-pregnant  cat,  at  the  junction  of  the 
partes  intermedia  and  nervosa,  210  days  after  oophorectomy,  showing  secretion 
and  granular  bodies.     {Photomicrograph.) 

X  500. 


EFFECTS    ON   OVARIES    OF    PITUITARY   REMOVAL     195 

granular  cells  sometimes  seen  in  the  pars  nervosa,  and  much 
secretion  (fig.  129). 

Pars  nervosa.     There  are  no  granular  bodies. 

From  an  examination  of  a  large  number  of  specimens  I  am 
forced  to  the  conclusion  that  although  there  is  considerable 
increase  in  the  activity  of  the  anterior  lobe  and  pars  intermedia 
of  the  pituitary  after  oophorectomy,  yet  this  is  not  so  well 
marked  as  after  removal  of  the  thyroid.  In  some  cases,  such 
as  in  cat  5  of  my  series,  which  was  killed  after  an  interval  of  208 
days,  there  was  no  divergence  from  the  normal  ;  consequently 
my  observations  are  opposed  to  the  hypothesis,  which  many 
authorities  have  sought  to  establish,  that  genital  atrophy  is  the 
primary  cause  of  acromegaly  (hyperpituitarism).  Fichera1  be- 
lieves, as  the  result  of  his  experiments,  that  removal  of  the 
ovaries  causes  a  change  in  the  anterior  lobe  analogous  to  that 
produced  by  pregnancy.  My  experiments  give  some  evidence 
of  this  in  the  fact  observed  that  the  chromophobe  cells  present 
seem  to  be  large  and  active.  It  is  unsettled,  however,  whether 
removal  of  the  ovaries  produces  a  permanent  change  in  the 
pituitary,  although  it  is  certain  that  the  immediate  effect  of 
oophorectomy  is  to  cause  an  increase  in  the  secretory  activity 
of  the  anterior  lobe  and  of  the  pars  intermedia,  especially  in 
regard  to  the  eosinophil  cells. 

The  effects   on  the  ovaries  of  partial  removal  of  the 

pituitary 

As  we  have  seen,  the  work  of  Paulesco2  and  of  Crowe, 
Cushing  and  Homans3  demonstrated  beyond  doubt  that  the 
removal  of  a  large  portion  of  the  anterior  lobe  may  produce 
genital  atrophy.  These  observers  state  that  in  the  ovaries  the 
follicles  cease  to  develop,  and  that  subsequently  the  uterus  and 
other  parts  of  the  genital  tract  undergo  atrophy. 

Degeneration  is  also  stated  to  be  produced  in  the  germinal 
cells  of  the  testes  after  the  removal  of  the  major  portion  of  the 
pars  anterior  in  dogs. 

1  Fichera,  G.,  Polidinico,  Rome,  1905,  xii,  250,  299  and  319 ;  also  1910,  xvii,  333. 

2  Paulesco,  N.  C,  Lhypophyse  du  cerveau,  Paris,  1908. 

3  Crowe,  S.  J.,  H.  Cushing  and  J    Horaans,  Bull.  Johns  Hopk.  Hosp.,    1910, 
xxi,  127. 


196  PHYSIOLOGY 

In  connexion  with  my  own  experimental  operations  on  the 
pituitaries  of  bitches,  I  took  the  precaution  of  removing  pieces 
of  one  ovary  and  the  uterus  before  operating  on  the  pituitary. 
In  this  way  I  had  a  specific  control  in  each  case  with  which  to 
compare  the  organs  subsequently  to  operation. 

I  usually  found1  that  profound  changes  in  the  ovaries  fol- 
lowed extensive  partial  removal  of  the  anterior  lobe  (figs.  130,  a 


Fig.   130. 

Sections  of  the  ovaries  of  the  bitch  before  (a)  and  210  days  after  (b)  partial 
removal  of  the  pars  anterior. 

X  200. 

and  b)  and  compression  or  separation  of  the  stalk  (figs.  131,  A 
and  b).  The  primordial  ova  undergo  a  hyaline  degeneration  : 
instead  of  showing  chromatin  fibres  with  translucent  interstices, 
after  operation  the  whole  ovum  becomes  opaque  and  structureless. 
The  epithelium  of  the  Graafian  follicles  degenerates  and  dis- 
appears, leaving  an  empty  space  in  the  place  previously  occupied 
by  the  follicles.  The  stroma  becomes  dense  and  fibrous  ;  and 
I  found  a  total  disappearance  of  the  interstitial  cells  (figs.  130b 
and  131b). 

In   some   of   my   experiments    after   partial   resection  of   the 
anterior    lobe    the    ovaries    and    uterus    showed    no    retrograde 

1  Bell,  W.  Blair,  Quart.  Journ.  Exp.  Physiol,  1917,  xi,  77. 


EFFECTS    ON    OVARIES   OF    PITUITARY    REMOVAL     197 


Fig.  131a. 


Section  of  the  ovary  of  the  bitch  before  operation.      {Photomicrograph.) 


x  120. 


131b. 


Section  of  the  ovary  of  the  same  bitch   128  days  after  separation  of 

the  stalk  of  the  pituitary.     {Photomicrograph.)  X  120. 


198  PHYSIOLOGY 

changes,  although  possibly  they  did  not  develop  to  the  normal 
extent  in  the  interval  between  operation  and  death. 

Removal  of  the  posterior  lobe  alone  or  with  a  small  portion 
of  the  anterior  lobe  does  not  affect  the  development  of  the  ovaries 
in   the  slightest  degree  :    they  go   on  to   maturity  in  a  normal 


Fig.  132. 

Sections  of  the  ovaries  of  the  bitch  before  (a)  and  after  (b)  removal  of  the  pars 
posterior  of  the  pituitary.  The  lower  part  of  B  is  occupied  by  cells  of  a  corpus 
luteum. 

X60. 

manner  (figs.  132,  a  and  b)  ;  and  in  one  of  my  cases  the  bitch  came 
'  on  heat ',  and  took  the  dog,  but  without  becoming  pregnant. 


Effects  on  the  pituitary  of  removal  of  the  suprarenals 

Since  removal  of  both  suprarenals  is  always  fatal  in  a  few 
days  to  the  larger  animals,  such  as  the  cat,  rabbit  and  dog, 
it  is  impossible  to  obtain  experimental  evidence,  except  in 
regard  to   acute  results,  from  this  procedure. 

I  have,  however,  removed  one  suprarenal  from  cats  and 
rabbits  in  the  hope  of  producing  insufficiency.  This  I  was  unable 
to  do  to  any  obvious  or  marked  extent  except  in  two  cases.  In 
a  few  of   my  experiments   I   first  removed   one   suprarenal,   and 


Facing,  page  199]. 


PLATE    7. 


Section  of  the  pars  anterior  of  the  non-pregnant  cat  36  hours 
after  the  removal  of  both  suprarenals.  The  cells  for  the  most  part 
are  chromophobe,  but   here  and  there  eosinophil  cells  are  to  be  seen. 

X  500 
(Direct  colour  photomicrograph). 


EFFECTS  ON  PITUITARY  OF  SUPRARENAL  REMOVAL  199 

subsequently  the  second.  This  last  operation  was  always  fol- 
lowed by  the  death  of  the  animal.  In  some  of  these  cases 
I  observed  changes  in  the  pituitary  which  were  probably  the 
result  of  suprarenal  insufficiency1. 

The  following  are  illustrative  experiments  : — 

Experiment  I. — Suprarenal  removal:    Cat,  non-pregnant. 

September   11th.     Roth  suprarenale  removed. 

September  13th.  Death  occurred  in  spite  of  careful 
nursing  and  keeping  the  animal  in  a  warm  temperature. 

There  were  tremors  and  great  muscular  weakness. 

Interval  between  the  operation  and  death  :   36  hours. 

Histological  examination  of  the  pituitary: 

Anterior  lobe.  There  is  a  large  proportion  of  chromo- 
phobe cells,  with  a  comparatively  moderate  number  of 
eosinophil  cells  (plate  7).  In  many  places  the  nuclei  are 
small  and  darkly  stained,  and  they  stand  out  sharply. 

Pars  intermedia.  The  cells  are  discrete  ;  that  is  to  say. 
they  are  not  fused.  The  nuclei  stand  out  prominently  ; 
they  are  small  and  darkly  stained  (fig.  133).  A  few  granular 
bodies  can  be  seen  among  the  cells  of  the  pars  intermedia. 

Pars  nervosa.  The  nervous  portion  is  invaded  by  the 
cells  of  the  pars  intermedia  ;  and  the  appearance  produced 
is  that  of  nuclei,  with  the  cell-protoplasm  lost,  stranded 
among  the  neuroglia -cells  (fig.  134). 

Experiment  II. — Suprarenal  removal :  Cat,  non-pregnant. 

September  18rh.     Left  suprarenal  removed. 

November  6th.  All  but  the  very  small  fragment  of  the 
right  suprarenal  removed. 

November  8th.     Animal  died. 

Interval  between  first  operation  and  death  :    51  days. 

Histological  examination  of  the  pituitary  : 

Anterior  lobe. — There  is  a  large  proportion  of  chromo- 
phobe cells,  with  fewer  eosinophil  cells  than  in  the  first 
experiment.  The  nuclei  are  small,  round  and  darkly  stained. 
and  they  appear  to  stand  out  from  the  surrounding  cell 
protoplasm  (fig.  135). 

Pars  intermedia. — The  cells  arc  not  fused,  and  their 
nuclei  stand  out  very   prominently  (fig.   136). 

Pars    nervosa. — This    portion    is    much     invaded    by    the 
1  Bell,  W.  Blair,  Arris  and  Gale  Lectures  :  Lancet,  1913,  i,  937. 


200 


PHYSIOLOGY 


•\  \ 


• 


*■*_    *         ^  •       J    iff 


•      ' 


•  v 


Fig.  133. 

Section    of    the    pars  [posterior    of   the  cat  36  hours   after  removal   of    both 

suprarenale,    showing    invasion   of    the    pars   nervosa    by    the  cells  of  the  pars 

intermedia.     {Photomicrograph.)  X  140. 


* ~    ♦   * 


• 


$         e 


"    % 


»v         * 


•     *>. 


s  t 

«.        • 


V-'       , 

a  •        «      w 


Fig.  134. 


Section  of  the  pars  nervosa  of  the  pituitary  of  the  cat  36  hours  after  removal  of 
the  suprarenals,  showing  invasion  of  the  pars  nervosa  by  cells  from  the  pars  inter- 
media, and  the  stranding  of  their  nuclei.  X  200. 


EFFECTS  ON  PITUITARY  OF  SUPRARENAL  REMOVAL  201 


Fig.  135. 

Section   of  the  pars  anterior  of  the  cat  after  removal  of  the  suprarenals,  showing 
chromophobia  of  the  cells,  the  nuclei  of  which  show  chromatosis.    (Photomicrograph.) 

X  400. 


\  • 


••** 


Fig.  136. 

Section  of  the  pars  posterior  of  the  cat  after  removal  of  the  suprarenals, 
showing  well-defined  cells  in  pars  intermedia,  and  invasion  by  these  cells  of  the 
pars  nervosa,  and  the  stranding  of  the  nuclei.     [Photomicrograph.) 

X  140. 


202  PHYSIOLOGY 

cells  of  the  pars  intermedia  (fig.  136),  which  present  an 
exactly  similar  appearance  to  that  seen  in  the  former  case 
(fig.   133). 

The  changes,  then,  in  the  pituitary  of  the  cat  that  appear 
constant  with  suprarenal  insufficiency,  acute  or  chronic,  are, 
first,  an  increased  chromophobia  of  the  cells  of  the  pars  anterior  ; 
second,  a  peculiar  smallness  and  chromatosis  of  the  nuclei,  to 
some  extent  in  the  anterior  lobe  but  most  definitely  in  the  pars 
intermedia,  the  cells  of  which  are  discrete  ;  and  third,  a  rapid 
and  extensive  invasion  of  the  pars  nervosa  by  the  cells  of  the 
pars  intermedia.  Many  of  these  cells  appear  to  lose  their  cell- 
protoplasm,  and  the  nuclei  in  consequence  are  left  stranded 
(figs.  133,   134  and  136). 


Effect  of  removal  of  the  pituitary  on  the  suprarenals 

Exact  observations  from  this  point  of  view  have  not  been 
obtained,  dishing1  states  that  in  experimental  forms  of  hyper- 
pituitarism (presumably  injection  experiments,  but  details  are 
not  given)  there  is  a  condition  of  vacuolation  of  the  zona  fascic- 
ulata  of  the  suprarenal  cortex,  as  I  have  found  after  ingestions 
of  an  extract  of  the  anterior  lobe  ;  but  this  author  also  states  that 
the  same  condition  is  observed  after  extirpation  of  the  pituitary. 
In  my  own  experiments  on  the  pituitary  I  was  unable  to  detect 
definite  changes  in  any  part  of  the  suprarenals  after  operation. 

I  have  seen  this  lipoid  (?),  or  secretory,  change,  mentioned  by 
dishing,  after  removal  of  the  ovaries,  and  during  pregnancy  ; 
so,  as  the  extent  of  it  varies  in  different  individuals  of  the  same 
species  in  normal  circumstances,  any  specific  cause  assigned  to 
such  a  condition  must  be  received  with  caution.  It  has,  too, 
been  stated  that  a  similar  change  occurs  in  the  secretory  and 
collecting  tubules  of  the  kidney  after  extirpation  of  ductless 
glands  ;  and  I  myself  have  observed  this  after  some  of  my 
experiments,  but  as  I  subsequently  found  the  same  change  in  the 
kidneys  of  control  animals,  especially  when  they  had  been  killed 
with,  chloroform,  I  was  compelled  to  acknowledge  the  absence 
of    specific    causation.     These    vacuolations    require    much    more 

1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


EFFECTS  ON  SUPRARENALS  OF  PITUITARY  REMOVAL  203 

careful  observation  by  means  of  differential  stains,  before  we 
can  discuss  them  with  profit.  Meanwhile,  I  have  no  suggestions 
to  make  as  to  the  exact  nature  of  the  condition,  which  is  probably 
less  abnormal  in  animals  than  is  usually  believed. 


The  pituitary  and  the  other  internal  secretory  organs 

There  is  a  certain  amount  of  material  available  concerning 
the  interrelationships  between  the  pituitary  and  the  pancreas  and 
thymus. 

Pancreas. — Cushing  and  his  fellow-workers1  first  advanced  the 
view  that  the  carbohydrate-tolerance  observed  in  hypopituitarism 
is  due  to  disturbance  of  the  internal  secretion  of  the  pancreas. 
Later,  after  more  pathological  experience,  Cushing  withdrew  this 
opinion  and  attributed  the  tolerance  to  insufficiency  of  the 
posterior  lobe2. 

It  appears,  however,  that  even  the  last  view  is  not  entirely 
correct  ;  consequently  the  results  of  the  researches  that  are  now 
being  conducted  by  Cushing  and  his  colleagues  on  this  subject 
are  awaited  with  interest. 

In  my  experiments  on  the  pituitaries  of  dogs  I  always  found 
the  pancreas  normal,  but  in  an  actively  secreting  state,  subse- 
quently to  the  operation.  Sweet  and  Allen3  lay  particular  stress 
on  a  similar  finding. 

I  have  already  referred  to  the  effect  of  injections  of  infund- 
ibulin  on  pancreatic  secretion  (p.  119). 

Pancreatectomy  is  said  by  Cushing4  to  produce  changes  in 
the  posterior  lobe  of  the  pituitary.  This  observation  is.  I  believe, 
unconfirmed. 

Thymus. — -Very  little  is  known  from  an  experimental  point 
of  view  of  the  relationship  between  the  thymus  and  the 
pituitary.  In  my  experiments  on  the  pituitary  I  found  in  most 
cases,  regardless  of  the  actual  lesion,  that  the  thymus  was  in 
an   active  state,  as  indicated   by  the  embryonic  and  unwhorled 


1  Goetsch,  E.,  H.  Cushing   and    C.  Jacobson,  Bull.  Johns  Hopk.  Hosp.,  1911, 
xxii,  165. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  19 1 2. 

a  Sweet,  J.  E.,  and  A.  R.  Allen,  Ann.  Surg.,  1913,  lvii,  485. 
4  Cushing,  H.s  Amer.  Joum.  Med.  Sci.,  1910,  xxxix,  473. 


204  PHYSIOLOGY 

character   of  the   epithelium  in  Hassall's   corpuscles  (fig.  137)- 
a  normal  condition  in  young  animals. 


Fig.  137. 

Section  of  the  thymus  of  the  bitch,  showing  unwhorled  epithelial  cells. 

{Photomicrograph.)  X  120. 


DISCUSSION    OF    THE    RESULTS    OF    REMOVAL    OF    THE    VARIOUS 
HORMONOPOIETIC    ORGANS 

The  interpretation  of  all  these  experimental  facts  is  not  easy, 
and  involves  a  short  reconsideration  of  the  whole  question  of 
increased  activity  in  the  pituitary. 

As  already  stated,  I  believe  that  the  three  types  of  cells  found 
in  the  anterior  lobe  represent  different  phases  of  secretory  activity. 
If  there  be  not  much  immediate  demand  for  the  secretion  of  the 
anterior  lobe,  in  the  higher  mammals  a  basophil  condition  of 
some  of  the  cells  is  found.  From  these  cells  basophil  colloid 
is  formed  for  storage  purposes.  After  yielding  up  their  secretion 
the  basophil  cells,  as  we  have  seen,  appear  as  shrunken  chromo- 
phobe cells.  These  in  time  become  eosinophil,  before  ultimately 
again  becoming  basophil. 

Now,  the  greatest  demands  on  the  secretion  of  the  anterior 
lobe  occur  normally  in  pregnancy,  and  experimentally  after 
removal  of  the  thyroids  and  suprarenals.     In  both  circumstances 


HORMONOPOIETIC    INTERRELATIONS  205 

we  find  what  may  be  called  '  active  chromophobe  '  cells — chromo- 
phobe cells,  that  is,  which  deliver  up  their  secretion  without  going 
through  the  further  phases  of  eosinophilia  and  basophilia. 

Next  in  secretory  activity  is  the  phase  of  eosinophilia  which  is 
an  intermediate  condition,  and,  as  a  result,  many  eosinophil  cells 
are  usually  present. 

After  removal  of  the  thyroid,  especially  when  the  condition  of 
insufficiency  is  chronic,  the  preponderance  of  eosinophil  cells  is 
most  pronounced.  In  such  circumstances  we  may  conclude  that 
the  demand  for  secretion  is  not  very  urgent,  and  there  is  time 
for  fully  formed,  normal,  secretion  to  be  delivered. 

There  can  be  little  doubt  that  the  secretion  of  the  '  pregnancy 
cells  '  and  of  the  artificially  produced  '  active  chromophobe  ' 
cells  is  similar,  and  is  an  emergency  substance.  And  since  in 
these  circumstances  the  secretion  is  abstracted  from  the  cells 
as  fast  as  it  is  formed,  there  is  no  collapse  of  the  cell — they 
remain  '  on  duty  ',  as  it  were.  If  the  demand  be  less  urgent 
eosinophilia  develops  in  the  contents  of  the  cells.  This  is  normally 
the  active  condition  of  the  cells  which  deliver  the  secretion  of  the 
anterior  lobe  ;  while  in  times  of  plenty  in  the  higher  mammals 
the  further  phase  of  basophilia  develops.  These  basophil  cells 
eventually  burst,  basophil  colloid  is  poured  out  and  the  collapsed 
cells  represent  the  shrunken  chromophobe  cells,  as  already  stated. 

These  points  have  been  reiterated  because  it  is  important 
to  emphasize  them,  and  to  show  their  bearing  on  the  present 
discussion. 

If  my  observations  be  correct  they  afford  evidence  concern- 
ing the  '  secretory-phase  hypothesis  ' — if  so  it  may  be  called — 
in  which  many  believe,  but  which  has  not  been  previously 
described  in  similar  detail. 

These  observations  offer,  too,  the  only  explanation  of  the  fact 
that  basophil  cells  do  not  occur  prominently  in  the  lower  mam- 
malian orders  in  which  no  doubt  the  anterior  lobe  is  normally 
more  active  than  in  higher  orders. 

With  regard  to  the  number  of  nuclei — apparently  bereft  of 
cellular  protoplasm — in  the  pars  nervosa  after  the  production 
of  suprarenal  insufficiency,  it  is  probable  that  the  protoplasm 
and  its  contained  secretion  have  been  rapidly  utilized  before  the 
nuclei  themselves  have  had  time  to  disappear.  This  is  borne 
out  by  the  fact,  previously  recorded,   that  the  granular  masses 


206  PHYSIOLOGY 

of  secretion  not  infrequently  seen  in  the  pars  nervosa  in  norm- 
al circumstances,  at  first  possess  nuclei  which  subsequently 
disappear. 

Thus  far,  therefore,  monoglandular  removals  have  helped 
us  to  solve  some  of  the  mysteries  concerning  the  physiology 
of  the  pituitary  body.  Later,  we  shall  consider  this  same 
question  of  the  internal  secretion  in  relation  to  the  pathology 
of  this  organ. 

It  would  have  been  a  satisfactory  conclusion  to  this  section, 
concerning  the  interrelationship  between  the  pituitary  and  the 
rest  of  the  hormonopoietic  system,  if  it  had  been  possible  to 
give  a  definite  and  lucid  exposition  of  the  exact  dependence 
each  has  on  the  secretion  of  the  rest.  Our  information,  how- 
ever, is  too  fragmentary  and  unsatisfactory  for  such  a  disquisi- 
tion, yet  I  cannot  help  feeling  that  the  day  is  not  far  distant 
when  we  shall  be  in  a  position  to  describe  this  part  of  the  subject 
with  comparative  comprehensiveness  and  certainty. 

Too  little  attention  has  been  paid  to  those  secretory  organs 
which  do  not  easily  and  certainly  yield  so-called  '  physiologically 
active  '  secretions — that  is,  an  active  extract  which  will  produce 
an  immediate  physiological  effect.  No  doubt  we  have  been 
hampered  by  technical  and  experimental  difficulties,  such  as 
are  encountered  in  the  removal  of  certain  parts  of  organs — for 
example,  the  suprarenal  cortex. 

Meanwhile  there  are  two  other  lines  of  very  profitable  in- 
vestigation, one  physiological  and  the  other  pathological.  We 
require  more  information  in  regard  to  the  activation  of  the  so- 
called  '  inactive  '  organs  :  in  other  words,  we  must  identify  the 
hormones.  It  is  probable  that  the  secretions  of  these  so-called 
'  inactive  '  organs  are  active  enough  when  combined  with,  or 
stimulated  by,  one  or  other,  or  by  several,  of  the  other  internal 
secretions.  In  seeking  to  discover  the  reason  of  the  uncertainty 
of  action  of  the  ovarian  extract  I  found  that  this  preparation 
is  much  more  active  when  thyroid  extract  is  administered  at  the 
same  time.  The  second  line  of  investigation  is  an  easy  one.  It 
consists  of  careful  histological  examinations  of  the  whole  hormono- 
poietic system  in  all  cases  of  disease  of  one  or  more  members  of 
the  series.  Many  deaths  occur  yearly  from  these  lesions,  yet  there 
exists  no  study  of  importance  from  this  pathological  point  of  view. 


THE    EFFECTS    OF    INOCULATIONS    WITH    BACTERIA 

Although  a  certain  amount  of  work  has  been  done  from  the 
clinicopathological  point  of  view  in  regard  to  the  changes  in 
the  pituitary  as  a  result  of  infections,  extremely  little  experi- 
mental work  has  been  carried  out.  Delille1  refers  to  the  striking 
hyperplastic  changes  to  be  observed  in  the  pituitaries  of  rabbits 
after  inoculations  with  typhoid  bacilli. 

I  have  conducted  a  series  of  inoculation  experiments  in 
guinea-pigs  with  tubercle,  colon  bacilli,  staphylococci  and 
streptococci. 

In  figures  63  (p.  86)  and  138  are  seen  the  normal  appearances 
of  the  pars  anterior  of  pregnant  and  non-pregnant  guinea-pigs, 
respectively.  In  the  pregnant  guinea-pig  there  is  marked  lobul- 
ation—the  so-called  adenomatous  disposition — of  the  chromo- 
phobe cells  (fig.  63).  In  the  non-pregnant  animal  (fig.  138)  the  cells 
present  a  more  uniform  appearance  of  eosinophilia.  In  figure 
139  is  shown  the  pars  anterior  of  a  non-pregnant  guinea-pig 
which  had  received  13  injections  of  an  emulsion  of  colon 
bacillus.  It  will  be  observed  that  there  is  hyperplasia  with 
considerable  increase  in  cell-contrast  and  definition.  Many  of 
the  cells  are  chromophobe,  and  vacuoles  containing  secretion 
are  plentiful  ;  the  appearance,  indeed,  is  not  unlike  that  seen 
in  the  pars  anterior  after  thyroidectomy. 

Staphylococcal  infections  produce,  in  most  cases,  a  more 
advanced  change.  The  blood-sinuses  appear  very  full,  and  in 
parts  of  the  pars  anterior  there  are  necrosis  and  disappearance 
of  many  of  the  cellular  elements.  For  the  most  part  the  eosino- 
phil cells  are  few,  and  where  necrosis  is  not  complete  faintly 
staining  chromophobe  cells  are  plentiful.  A  peculiar  feature 
is  the  survival  of  deeply  basophil  cells — normally  absent  in  the 

1  Delille,  A.  (quoted  by  Gushing,  H.,  The  Pituitary  Body  and  its  Disorders, 
1912). 


208 


PHYSIOLOGY 


«   S         Jjr,- 


,  »~    * 


s 


*#* 


Fig.  138. 

Section  of  the  pars  anterior  of  the  normal  non-pregnant  guinea-pig, 

micrograph. ) 


(Photo- 
X  400. 


-       L 


t 


•      • 


* •%r * * 


Fig.  139. 

Section  of  the  pars  anterior  of  the  guinea-pig  after  13  injections  of  an  emulsion 
of  colon  bacillus,  showing  chromophobia  with  increased  secretory  activity. 
( Photomicrograph. ) 

X400. 


THE  EFFECTS  OF  INOCULATIONS  WITH  BACTERIA  209 

guinea-pig — -which  consequently  appear  in  some  cases  to  domin- 
ate the  picture  (fig.  140). 

In  the  series  of  animals  dying  from  tuberculosis,  or  killed 
when  deeply  affected  by  this  disease,  three  were  pregnant  and 
six  were  non-pregnant.  It  is  important  always  to  take  into 
consideration  the  presence  or  otherwise  of  pregnancy  in  female 
animals,  since  the  normal  changes  during  gestation  are  con- 
siderable, as  already  indicated.  In  the  non-pregnant  animals  the 
cells  of  the  anterior  lobe  present  a  greater  degree  of  chromophobia 


m 


...- 


Fig.   140. 

Section  of  the  pars  anterior  of  the  guinea-pig  after  injections  of  an  emulsion  of 
staphylococcus,  showing  necrosis  with  survival  of  basophil  cells.     {Photomicrograph.) 

X  400. 

than  normal  ;  and  in  the  pregnant  animals  the  chromophobe 
cells  are  more  numerous,  more  indistinct,  and  apparently  larger 
than  normal.  The  nuclei  appear  brightly  and  distinctly  stained 
against  a  hazy  background  of  cell-cytoplasm.  But  on  the  whole 
the  tubercle  bacillus  affects  the  pars  anterior  less  than  is  the 
case  with  the  other  organisms. 

In  the  streptococcal  eases  there  is  very  well-marked  chromo- 
phobia, and  in  the  non-pregnant  animals  the  large  chromo- 
phobe cells  resemble  those  seen  in  pregnancy.     The   appearance 

14 


210  PHYSIOLOGY 

of  blurring,  also,  may  be  an  indication  of  increased  activity,  if  it 
be  not  a  sign  of  commencing  degeneration. 

The  changes,  then,  that  may  occur  in  the  pituitary  as  the 
result  of  experimental  inoculation  of  bacteria  vary  from  hyper- 
plasia of  the  eosinophil  cells  to  chromophobia  with  considerable 
increase  in  activity.  The  later  necrotic  changes  are  due  to 
direct  infection  of  the  gland  and  thrombosis  of  the  vessels. 

In  no  case  was  any  change  observed  in  the  pars  nervosa,  but 
in  the  pars  intermedia  there  usually  appeared  to  be  considerable 
activity  in  the  cells — that  is,  fusion  of  the  cell-bodies  ;  this,  of 
course,  we  should  expect  in  view  of  the  changes  in  the  pars 
anterior. 


THE    INTERPRETATION     OF    PATHOLOGICAL    PROCESSES 
AFFECTING    THE    NORMAL    PHYSIOLOGY 

The  method  of  studying  physiological  processes  through 
'  Nature's  experiments  '  is  one  of  the  greatest  value,  but  un- 
fortunately is  not  used  to  any  great  extent  by  physiologists  or 
clinicians,  probably  because  as  a  rule  neither  class  of  investi- 
gator is  sufficiently  acquainted  with  the  work  and  requirements 
of  the  other. 

I  shall  deal  very  briefly  with  the  subject  here,  for  the  facts 
on  which  my  arguments  will  be  based  are  set  out  in  more  detail 
in  the  next  part  of  this  work. 

Infections 

Infections,  whether  local  or  general,  cause  hyperplasia  in  the 
pars  anterior  ;  consequently  it  has  been  presumed  that  one  of 
the  normal  functions  of  the  pituitary  is  to  neutralize  toxins  which 
may  be  circulating  in  the  blood. 

Diseases  associated  with  pregnancy 

In  the  so-called  toxaemias  of  pregnancy  we  shall  observe 
abnormal  conditions  of  the  pituitary.  For  the  most  part  these 
indicate  that  this  organ  is  not  in  the  high  state  of  activity 
that  is  usual  during  pregnancy.  Possibly  this  leads  to  a 
condition  of  acidosis  ;  for  one  of  the  normal  functions  of  the 
pituitary  is  the  retention  of  alkaline  bases  in  the  tissues,  a 
state  of  affairs  which  is  directly  opposed  to  acid  intoxication. 

Diseases  of  the  hormonopoietic  system 

We  observe  in  pathology,  as  in  physiology,  close  relationships 
between  the  pituitary  and  the  other  organs  of  internal  secretion. 


212  PHYSIOLOGY 

Furnivall1  found  only  one  normal  thyroid  in  twenty-four  cases 
of  pituitary  lesions  which  he  had  collected  from  the  litera- 
ture, and  in  which  complete  records  were  given,  dishing2  in 
fifteen  cases  found  marked  excess  of  colloid  in  all  the  thyroids. 
Of  these  fifteen  cases  the  pituitary  condition  in  all  but  a  single 
case  was  one  of  insufficiency.  No  changes  were  found  in  the 
parathyroids. 

It  does  not  appear,  therefore,  that  the  thyroid  acts  vicariously 
for  the  pituitary,  as  has  been  suggested  by  some.  On  the  one 
hand,  there  is  evidence,  already  mentioned,  that  whole-gland 
pituitary  extract  stimulates  the  activity  of  the  thyroid.  On 
the  other  hand,  I  have  found  that  infundibulin  has  a  beneficial 
effect  on  hyperthyroidism. 

Schonemann3,  in  an  investigation  of  eighty -five  cases  of 
goitre,  found  '  marked  alterations  '  (no  details  are  given)  in  the 
pituitary. 

I  myself  have  observed  changes  in  the  pituitary  in  diseases 
of  the  thyroid  which  indicate  that  the  pars  anterior  acts  in  a 
complementary  fashion  so  far  as  the  thyroid  is  concerned,  and 
that  the  activity  of  the  former  is  related  to  the  relative  insuffic- 
iency of  the  latter. 

Regarding  the  relation  of  the  pituitary  to  the  gonads,  we 
have  evidence  that  in  acromegaly  there  may  be  stimulation  of 
the  male  genital  organs.  This,  however,  is  only  observed  in  the 
early  stages  of  the  disease.  I  shall  mention  a  case  later  in 
which  hypertrophy  of  the  clitoris  occurred  in  a  woman  with  this 
disease. 

In  view  of  the  physiological  and  pathological  evidence  at 
our  disposal  we  may  assume  that  lesions  and  removal  of  the 
pituitary  have  a  far  more  pronounced  effect  upon  the  genital 
glands  than  the  extirpation  of  these  organs  has  upon  the  pituitary. 

The  pathological  evidence  of  a  relationship  between  the 
pituitary  and  suprarenals  is  very  slight,  although  it  is  impossible 
not  to  recognize  in  many  cases  of  hyperpituitarism  a  plurigland- 
ular syndrome,  for  acromegaly  may  be  accompanied  by  mani- 
festations resembling  Addison's  disease. 

1  Furnivall,  P.,  Trans.  Path.  Soc.,  1898,  xlix,  204. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

3  Schonemann,  A.,  Virchow,s  Arch.  f.  Pathol.  Anat.  u.  Physiol.,  1892,  exxix, 
310. 


INFLUENCE   OF   PATHOLOGICAL   CONDITIONS     213 

It  is  possible,  therefore,  that  in  hyperpituitarism  (acromeg- 
aly), in  which  there  is  an  excess  of  secretion,  the  suprarenals 
become  inactive,  and  that  in  hypopituitarism  (dystrophia 
adiposogenitalis)  suprarenal  activity  increases.  This,  at  any 
rate,  is  the  interpretation  dishing  places  on  the  results  of  his 
extirpation  experiments.  In  my  own  I  failed  to  observe 
definite  changes  in  the  suprarenals  after  operations  on  the 
pituitary;  and  I  do  not  think  the  second  conclusion  is  justified 
by  the  clinical  evidence  at  our  disposal  in  regard  to  hypo- 
pituitarism. 

We  have  very  little  pathological  information  that  throws 
any  light  on  the  normal  relationships  of  the  pancreas,  the  pineal 
and  the  thymus  to  the  pituitary — certainly  nothing  that  calls  for 
discussion  here. 


§  iii.   COMPARATIVE    PHYSIOLOGY 

Very  few  words  are  necessary  to  describe  the  comparative 
physiology  of  the  pituitary. 

We  have  seen  that  in  all  vertebrates  higher  than  the  elasmo- 
branchs  there  is  a  definite  pars  nervosa  ;  and  it  has  been  found 
that  extracts  made  from  this  structure,  or  from  the  whole  gland 
containing  this  part,  are  active  in  all  the  respects  already  de- 
scribed. For  our  information  on  this  subject  we  are  chiefly 
indebted  to  the  work  of  Herring1.  This  observer  has,  moreover, 
noted  the  extremely  interesting  fact  that  although  the  pituitary 
of  the  skate  (elasmobranch)  contains  no  pars  nervosa,  and  that, 
therefore,  an  extract  of  the  gland  gives  none  of  the  well-known 
pressor  effects  associated  with  the  action  of  infundibulin,  yet  the 
extract  made  from  the  epithelial  portion  has  a  definite  augmenta- 
tive effect  on  the  flow  of  milk  from  the  mammae  of  a  lactating 
animal. 

This  same  result  was  obtained  with  an  extract  made  from 
the  epithelial  portion  of  the  pituitary  of  the  cod,  but  there  was 
also  a  rise  in  blood-pressure,  and  this,  as  Herring  justly  says,  may 
indicate  the  inclusion  of  some  of  the  extract  of  the  pars  nervosa 
which  is  present  in  teleosts. 

Further  investigations  are  required  to  confirm  and  extend 
these  interesting  observations,  especially  in  regard  to  the 
acquisition  of  evidence  which  might  further  indicate  that  it  is 
the  epithelial  portion  which  dominates  the  functions  of  the 
pituitary. 

The  investigations  of  Halliburton,  Candler  and  Sikes2,  and 
of  A.  S.  Griinbaum  and  Helen  Grunbaum3,  have  shown  that  the 
extract  of  the  pars  posterior  of  the  human  pituitary  has  physio- 
logical actions  similar  to  those  produced  by  the  same  extract 
from  other  vertebrate  animals. 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol.,  1908,  i,  261  ;  idem.,  1913,  vii,  73. 

2  Halliburton,  W.  D.,  J.  P.  Candler,  and  A.  W.  Sikes,  Quart.  Journ.  Exper. 
Physiol.,  1909,  ii,  229. 

3  Grunbaum,  A.  S.,  and  Helen  G.  Grunbaum,  Journ.  Physiol.  (Proc.  Physiol. 
Soc. ),  1911,  xlii,  x.wiii. 


PART    III 

DISORDERS 

ASSOCIATED    WITH 

THE    PITUITARY 

AND    THEIR 

TREATMENT 


PART    III 

DISORDERS    ASSOCIATED    WITH    THE 
PITUITARY    AND    THEIR    TREATMENT 

It  was  not  till  the  year  1886  that  pathological  lesions  of  the 
pituitary  body  were  recognized  and  associated  with  clinical 
manifestations.  In  that  year  Marie1  described  changes  in  this 
organ  in  the  disease  known  as  'acromegaly'  (anpog  =  extremity, 
and  fiiyag,  /ayuX-  =  large).  In  the  following  year,  possibly  inde- 
pendently, Minkowski2  described  in  more  detail  the  relationship 
between  acromegaly  and  lesions  of  the  pituitary.  Since  then 
many  investigators  have  not  only  confirmed  this  pioneer  work 
and  elucidated  the  finer  points  in  the  histopathology  of  acromeg- 
aly, but  have  extended  their  observations  to  other  morbid 
conditions  arising  from  disordered  states  associated  directly  or 
indirectly  with  the  pituitary  body. 

The  earlier  investigators  were  hampered  considerably  in 
drawing  their  conclusions  by  lack  of  definite  information  con- 
cerning the  anatomy  and  physiology  of  the  pituitary.  Even 
in  the  present  day  there  is  considerable  doubt  whether  the 
pituitary  body  should  be  considered  one  organ  or  two  organs  ; 
and  we  shall  see  that  many  of  the  difficulties  in  regard  to 
the  interpretation  of  pathological  phenomena  have  arisen  from 
this  uncertainty  concerning  the  unity  or  duality  of  the 
pituitary. 

There  is,  too,  in  regard  to  the  normal  physiology,  another 
serious  obstacle  that  confronts  those  who  are  not  fully  satisfied 
with  merely  recording  disjointed  facts  :  I  refer  to  the  imper- 
fections in  our  knowledge  concerning  the  undoubted  correlations 

1  Marie,  P.,  Rev.  de  Med.,  1886,  vi,  297. 

2  Minkowski,  O.,  Berl.  Klin.   Woch.,  1887,  xxiv,  371. 


216    DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

that  exist  between  the  pituitary  and  the  other  hormonopoietic 
organs.  This  lack  of  comprehension  often  prevents  our  knowing 
whether  certain  symptoms  are  due  to  primary  pituitary  disease 
or  to  associated  changes  in  some  other  of  the  organs  of  internal 
secretion.  This  is  a  difficulty  which  is  likely  to  trouble  us  for 
some  time — until  far  more  work  has  been  done  on  the  inter- 
relationships between  the  internal  secretions.  Meanwhile,  no 
good  can  come  of  attempting  to  disguise  the  ill-defined,  if  not 
chaotic,  state  of  our  acquaintance  with  the  subject.  Further, 
a  clear  conception  of  the  gaps  in  our  knowledge  is  necessary 
before  we  can  identify  with  certainty  the  established  facts  that 
stand  out  from  the  host  of  other  obscurer  details  with  which  the 
subject  is  burdened. 

The  recognition,  then,  of  acromegaly  as  a  primary  disease  of 
the  pituitary  body  first  turned  the  attention  of  clinicians  to  this 
organ  ;  but  it  was  not  until  Tamburini1  showed  that  there  may 
be  two  stages — hyperpituitarism  and  hypopituitarism  —asso- 
ciated with  acromegaly,  and  Frohlich2  described  the  condition 
of  dystrojyhia  adiposogcnitalis  (hypopituitarism),  that  many 
hitherto  little  understood  and  apparently  contradictory  facts 
became  intelligible. 

Much  more  recently  Cushing3  has  described  all  conditions 
of  perverted  pituitary  function  as  *  dyspituitarisms ' ;  and  he 
subdivides  these  into  five  clinical  or  symptomatic  groups4. 

From  a  scientific  point  of  view,  as  wrell  as  for  the  sake  of 
lucidity,   it   appears  to   me   better  to   consider   pituitary   lesions 

1  Tamburini,  A.,  Riv.  Speriment.  di  Freniat.,  1894,  xx,  559. 

2  Frohlich,  A.,  Wien.  Klin.  Bundsch.,  1901,  xv,  883. 

3  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

4  The  following  are  the  groups  described  by  Cushing  : — 

"  1.  Cases  of  dyspituitarism  in  which  not  only  the  signs  indicating  distortion 
"  of  neighbouring  structures,  but  also  the  symptoms  betraying  the  effects  of  altered 
"  glandular  activity  are  outspoken. 

"  2.  Cases  in  which  the  neighbourhood  manifestations  are  pronounced,  but 
"  the  glandular  symptoms  are  absent  or  inconspicuous. 

"  3.  Cases  hi  which  neighbourhood  manifestations  are  absent  or  inconspicu- 
"  ous,  though  glandular  symptoms  are  pronounced  and  unmistakable. 

"  4.  Cases  in  which  obvious  distant  cerebral  lesions  are  accompanied  by  symp- 
"  tomatic  indications  of  secondary  pituitary  involvement. 

"  5.  Cases  with  a  polyglandular  syndrome  in  which  the  functional  disturb- 
"  ances  on  the  part  of  the  hypophysis  are  merely  one,  and  not  a  predominant 
"  feature,  of  a  general  involvement  of  the  ductless  glands." 


DISORDERS   ASSOCIATED   WITH   THE  PITUITARY     217 

as  primary,  and  as  secondary  to  disease  in  the  neighbourhood, 
to  general  disorders  or  to  derangements  of  the  other  organs  of 
internal  secretion  ;  and,  also,  in  each  case  according  to  whether 
there  is  a  condition  of  excess  of  secretion  or  deficiency— so  far, 
at  any  rate,  as  our  knowledge  will  allow  such  an  estimation. 


§  i.    PRIMARY   LESIONS    OF    THE   PITUITARY 


HYPERPITUITARISM1 

Many  authors  do  not  state  whether  they  consider  that  in  hyper- 
pituitarism only  the  epithelial  elements  are  concerned ;  most, 
however,  infer  it.  In  the  recent  work  of  Cushing2  the  relative 
importance  of  the  anterior  and  posterior  lobes  is  not  made  suffic- 
iently clear  ;  indeed,  this  surgeon  in  the  work  mentioned  con- 
tradicts the  results  of  his  previously  published  experimental 
observations. 

A  normal  condition  of  hyperhypophysism3  exists  in  pregnancy, 
as  already  described  ;  and  there  are,  also,  fluctuations  in  the 
functional  activity  of  the  pars  anterior,  as  of  other  ductless 
glands,  at  various  periods  of  life,  in  accordance  with  the  state 
of  the  metabolism  in  regard  to  growth,  reproduction  and  decay. 

It  is  still  a  debated  point  whether  a  pathological  state  of 
hyperhypophysism  is  due  merely  to  an  increase  of  secretion,  or 
whether  the  secretion  is  also  a  perverted  one.  There  is  con- 
siderable evidence  in  favour  of  the  latter  view,  and  no  one  has 
succeeded  in  producing  the  symptoms  of  hyperhypophysism  by 
the  administration  of  hypophysial  extracts  to  the  human  subject 
or  to  animals. 

The  results  of  pathological  hyperhypophysism  (an  expression 
which  we  will  consider  admits  the  possibility  of  a  perverted 
function)  depend  on  the  period  of  life  at  which  the  lesion  becomes 
manifest,  and  also  on  the  extent  of  departure  from  the  normal 
in  regard  to  the  secretion. 

When  there  is  hyperplasia  of  the  anterior  lobe  in  early  life 
the  effect  produced  depends  on  the  sex  of  the  patient.  If  the 
subject  be  a  boy  sexual  precocity  may  occur.  In  the  cases  on 
record  the  evidence  is  generally  incomplete  or  conflicting  as  to 

1  '  Hyperpituitarism '  implies  abnormal  activity  of  the  whole  organ. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

3  '  Hyperhypophysism '  implies  abnormal  activity  of  the  partes  anterior  and 
intermedia. 


HYPERPITUITARISM  219 

whether  the  pineal  may  not  have  been  concerned1,2 ;  but  the 
fact  that  in  girls  hyperplasia  of  the  pars  anterior  leads  to  the 
manifestations  of  precocious  masculinity — hypertrichosis,  a  deep 
voice  and  the  rest — gives  point  to  the  view  that  the  pituitary 
may  sometimes  be  concerned  in  the  way  indicated  in  regard  to 
masculine  precocity. 

When  the  onset  of  hyperhypophysism  occurs  before  the 
epiphyses  have  joined,  a  remarkable  growth  of  the  skeleton 
follows,  and  gigantism  results.  Subsequently,  the  typical  signs 
and  symptoms  of  acromegaly  may  appear. 

If  the  disease  commence  late  in  life  when  the  epiphyses  have 
joined,  then,  of  course,  gigantism  does  not  supervene,  but  certain 
typical  skeletal  changes  to  be  described  directly  are  to  be  seen. 

The  only  specific  disease  known  to  be  produced  by  hyper- 
pituitarism is  acromegaly,  for  although  gigantism  may  be  asso- 
ciated with  this  condition,  well-marked  skeletal  development 
cannot  be  considered  pathological  in  the  absence  of  acromegaly. 
It  may,  in  fact,  be  due  merely  to  adolescent  hyperhypophysism, 
just  as  one  sees  in  girls  hyperthyroidism  at  puberty — a  condition 
which  produces  a  temporary  effect  that  subsequently  subsides. 

ACROMEGALY 

Incidence  of  the  disease. — Acromegaly  occurs  more  com- 
monly in  women  than  in  men,  and  most  often  makes  its  appear- 
ance between  the  20th  and  40th  years.  It  is,  in  fact,  a  disease 
of  the  reproductive  period,  and  more  especially  of  that  immedi- 
ately following  puberty. 

In  some  cases  there  is  a  family  history  of  hyperhypophysism, 
especially  in  regard  to  skeletal  overgrowth. 

Symptoms,  signs,  and  course  of  acromegaly. — It  is  very 
difficult  to  say  what  are  the  prodromal  signs — apart  from  gigan- 
tism— if  such  exist.  But  among  the  earliest  definite  symptoms 
arc  slight  ocular  disturbances,  such  as  photophobia  ;  headache 
and  facial  neuralgia,  also,  are  not  uncommon,  and  there  is  usually, 
but  not  always,  muscular  weakness.     At  first,  the  patient  may  be 

1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Poynton,  F.  J.,  Proc.  Boy.  Soc.  Med.  {Neurol  and  Ophthalmol.  Sects.),  1913, 
vi,  xviii. 


r 


220     DISORDERS  ASSOCIATED  WITH   THE  PITUITARY 

restless,  and  in  men  the  sexual  appetite  is  sometimes  increased1,2. 
A  little  later,  manifestations  may  occur  as  the  result  of  the  impli- 
cation of  other  organs  of  internal  secretion.  In  men  there  may 
be  impotence,  and  in  women  there  is  inevitably  amenorrhcea 
and  usually  sterility.  Not  infrequently,  however,  there  are 
periods  of  abatement  in  the  disease,  during  which  the  sexual 
functions  become  reestablished.  This  interesting  phenomenon 
shows  us  that  actual  atrophy  of  the  genital  organs  does  not  occur 
— at  any  rate  until  late  in  the  disease. 

Another  very  striking  train  of  events  in  connexion  with 
acromegaly  in  women  is  the  tendency  towards  masculinity.  The 
bones  become  enlarged,  the  voice  deep,  the  skin  coarse  and  the 
features  heavy.  In  one  case  which  came  under  my  notice  there 
was  considerable  hypertrophy  of  the  clitoris,  and  this  caused 
the  patient  much  mental  distress.  The  metabolism  is  directed 
towards  calcium  retention — an  essentially  masculine  characteristic3. 

The  amenorrhcea  with  which  women  suffer  in  acromegaly  is 
probably  due  to  this  change  to  masculinity,  and  not  primarily 
to  hyperpituitarism. 

The  alterations  which  take  place  in  the  skeleton  have  been 
studied  by  Keith4,  and  according  to  this  observer  the  results 
produced  are  due  to  a  hormone  secreted  by  the  pars  anterior. 
"  It  renders,"  he  says,  "  the  osteoblasts  hypersensitive  to  the 
various  stresses  which  fall  on  the  human  skeleton  during  life. 
Thus  the  osteoblasts  at  the  origins  and  insertions  of  muscles 
become  increasingly  sensitive  to  the  traction  of  the  muscle 
fibres  ;  the  muscular  impressions  and  processes  of  the  skeleton 
become  unduly  raised,  extended,  and  emphasized  by  the  forma- 
tion of  new  bony  matter  ".  Keith  reminds  us  that  John  Hunter 
showed  that  deposition  and  absorption  of  bone  go  hand  in  hand  ; 
and  he  himself  considers  that  in  acromegaly  the  coordination 
between  growth  and  absorption  is  lost. 

The  patient  with  acromegaly  soon  notices  that  the  hands, 
feet  and  head  are  becoming  enlarged  :  larger  boots  and  gloves 
are  required,  and  if  the  patient  be  a  man,  he  will  from  time  to 
time  need  larger  sizes  in  hats. 

1  Buday,  K.,  and  N.  Iansci,  Deutsch.  Arch.  f.  Klin.  Med,,  1898,  lx,  385. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

3  Bell,  W.  Blair,  The  Sex  Complex,  1916. 
*  Keith,  A.,  Lancet,  1911,  i,  993. 


ACROMEGALY 


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222     DISORDERS   ASSOCIATED   WITH   THE  PITUITARY 

Enlargement  of  the  vault  of  the  skull  can  be  recognized  in 
a  radiograph  by  the  increase  of  bone  on  the  superciliary  ridges, 
and  the  greater  size  than  normal  of  the  frontal  sinuses  (fig.  141). 

Likewise  the  enlargement  (fig.  142)  and  often  deformation  of 
the  sella  turcica  become  noticeable  (figs.  143  and  144).  In 
acromegaly  there  may  be  thickening  of  the  clinoid  processes  and 


Fig.  142. 

Base  of  the  skull  in  a  case  of  acromegaly,  showing  the  greatly  enlarged  sella 
turcica.     {Photograph.) 

X\. 

dorsum  sellse,  as  of  the  other  bones  ;  but  eventually  there  is 
pressure-atrophy  with  thinning  of  the  bones  and  the  disappear- 
ance of  the  posterior  clinoid  process  (figs.  141,  143,  144). 

According  to  Johnston1  there  is  a  form  of   '  localized  acro- 
megaly '   in   which   epilepsy   is   a   common   symptom ;     and   this 

1  Johnston,  G.  C,  Atner.  Journ.  Roentgenol.,  1914,  i  (New  Ser.),  172. 


ACROMEGALY 


Fig.   143. 

Radiograph  of  the  skull  of  a  woman  suffering  with  acromegaly,  showing  enlargement 
and  deformation  of  the  sella  turcica.      {By  Tliurstan  Holland.) 

X  }. 


Fig.   144. 

Radiograph  of  the  skull  of  a  woman  suffering  with  acromegaly,  showing  the  dis- 
appearance of  the  posterior  clinoid  processes.     (By  Thuratan  Holland.) 

X  ]. 


224     DISORDERS   ASSOCIATED   WITH   THE  PITUITARY 

symptom,  his  radiographic  studies  lead  him  to  think,  is  due  to 
the  close  confinement  of  the  pituitary  by  the  overgrowing  clinoid 
processes  and  dorsum  sellae. 

The  changes  in  the  bones  of  the  extremities  can,  also,  easily 
be  recognized  in  a  radiograph  :    the  phalanges  become  widened 


Fig.   145. 

Acromegaly  in  a  woman.     The  features  are  thickened  and  heavy  and  the  hands 
are  splayed.     (Photograph.) 

and  the  terminal  bones  are  tufted  at  the  extremities  (fig.  146). 
These  alterations  cause  the  hands  to  become  broad  and  splayed 
(fig.  145). 

Gradually  the  face  becomes  distorted  :  the  malar  bones 
increase  in  size  and  the  lower  jaw  so  enlarges  that  it  may  project 
beyond  the  upper  (prognathism)  (figs.  145  and  147),  which  is 
itself  often  enlarged.     There  is,  however,  no  increase  in  the  size 


ACROMEGALY 


225 


Fig.  147. 

Profile-view  of  a  woman  suffering  with  acromegaly,  showing  prognathism. 

(Photograph.) 


v 


Fig.  14S. 


Separation  of  the  teeth  in  a  woman  suffering  with  acromegaly.     (Photograph.) 

15 


226    DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

of  the  palate.  The  maxillary  expansion  involves  the  whole 
circumference  of  the  jaws  and  causes  the  teeth  to  become  widely 
separated  (fig.  148) — a  very  constant  sign  of  the  disease. 

The  skin  becomes  coarse,  rough  and  thick  owing  to  hyper- 
trophy of  the  papillae  and  thickening  of  the  cutis  and  the  sub- 
cutaneous tissues,  and  it  may  be  yellowish  or  pigmented  ;  the 
hair  and  nails  become  brittle.  The  nose  and  ears  enlarge  and 
the  lower  lip  becomes  bulky  and  pendulous  (fig.  145),  as  the 
result  of  the  changes  mentioned  in  the  cutaneous  and  sub- 
cutaneous tissues.  Likewise  there  is  an  increase  in  the  size  of 
the  tongue ;  and  the  mucous  membrane  of  the  nose  and  pharynx 
becomes  thickened.  The  enlargement  of  the  tongue  may  cause 
the  patient  to  keep  the  mouth  always  open,  and  the  thickening 
of  the  nasal  mucosa  gives  rise  to  discomfort  and  difficulty  of 
breathing,  and  even  to  deafness  from  involvement  of  the 
Eustachian  tubes.  The  patient  often  suffers  with  polyuria,  and 
glycosuria,   the  result  of  hyperglycaemia,  is  sometimes  present. 

Unless  the  disease  become  arrested — as  not  infrequently 
happens— various  other  symptoms  soon  make  their  appearance  : 
the  patient  complains  of  tinnitus  auriuni,  and  invariably  of  the 
severity  of  the  'pituitary  headache'  which  results  from  pressure 
in  the  pituitary  fossa,  of  giddiness,  unsteady  gait  and  occa- 
sionally of  epileptiform  seizures  ;  and  there  is  usually  progressive 
lassitude  and  torpidity,  although  sometimes  the  psychical  func- 
tions remain  undisturbed  until  an  advanced  stage  of  the  dis- 
ease. Vomiting  due  to  intracranial  pressure  is  rare,  but  may 
occur. 

Simultaneously  with  the  symptoms  just  described,  or  later, 
the  patient  complains  of  serious  disturbances  of  vision.  On 
examination,  various  degrees  of  divergence  from  the  normal, 
according  to  the  extent  of  the  intracranial  injury  to  the  optic 
tracts,  are  found.  Bitenmoral  hemianopia  is  usually  present 
early  in  the  disease  (fig.  149),  but  is  often  undiscovered  at  first 
by  the  patient,  owing  to  the  fact  that  colour-vision  disappears 
before  the  white  field  (fig.  150,  a).  Sometimes  there  is  diplopia  ; 
and  even  external  strabismus  from  injury  of  the  third  nerve 
is  not  uncommon.  Eventually  the  fields  of  vision  may  become 
extremely  restricted  (fig.  150,  b),  and  finally  blindness  may  super- 
vene from  atrophy  of  the  optic  nerves.  Extensive  involvement, 
however,   of  the  optic  tracts  and  of   the  oculomotor    nerve    is, 


ACROMEGALY 


227 


according    to    Gushing1,    uncommon    in    acromegaly.     Sometimes 
there  is  exophthalmos. 

This  train  of  events,  short  in  the  description,  takes  long  in 
the  development.  Patients  suffering  with  acromegaly  live  for 
many  years  in  a  condition  of  hyperhypophysism,  but  most  of 
them  drift  finally  into  the  condition  of  hypohypophysism  which 
I  shall  describe  presently,  and  this  occasionally  after  a  period 
of  apparent  quiescence  in  the  disease.  In  very  rare  cases  when 
acromegaly  has  been  due  to  a  functionating  malignant  tumour 
of  the  anterior  lobe  the  disease  runs  a  rapidly  fatal  course2. 


Fig.  149. 

Restricted  white  fields  of  vision  in  a  case  of  acromegaly.      {By  T.  H.  Bickerlon.) 


As  we  have  seen,  during  pregnancy  the  activity  of  the 
anterior  lobe  is  normally  increased,  and,  as  a  result,  minor  and 
temporary  symptoms  of  acromegaly  may  occasionally  occur, 
especially  thickening  of  the  subcutaneous  tissues.  Marek3  has 
reported  a  case  in  which  acromegaly,  with  glycosuria,  prognathism 
and  some  of  the  other  symptoms  of  the  disease,  commenced 
during  pregnancy  and  disappeared  during  the  puerperium. 

The  metabolism  in  acromegaly. — Observations  concerning 
the  metabolic  disturbances  in  acromegaly  are  so  conflicting  that 
it  is  probable  that  many  of  the  abnormalities  found  depend  not 

1  Gushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

-  Fischer,  B.,  Hypophysis,  Akromegalit  und  Fettsucht,  Wiesbaden,  1910. 

3  Marek,  R.,  Zenlralbl.f.  Uynak.,  1911,  xxxv,  1612. 


228      DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 


White        right 
Red 


White 
Red 


90  90 


White  RIQHT. 

Red 


90  SO 


Fig.   150. 

Fields  of  vision  (colour  and  white)  in  a  case  of  acromegaly,  a,  on  December 
18th,  1911,  when  the  colour-fields  were  greatly  restricted,  and  the  white  fields  only 
slightly,  b,  on  February  17th,  1913,  when  the  white  fields  were  much  limited 
and  the  colour-fields  less  than  previously.     (Doyne.) 


ACROMEGALY 


229 


only    on    hypophysial    disease,    but    also     on    a    pluriglandular 
syndrome. 

Franchini1,  and  Franchini  and  Giglioli2  investigated  several 
cases  of  acromegaly  and  concluded  that  in  the  active  stages  of 
the  disease  there  is  an  excessive  excretion  of  nitrogen  and 
phosphorus,  and  a  considerable  retention  of  calcium  and 
magnesium.  These  observers  state  that  the  metabolism  of 
chlorine,  sodium,  and  potassium  is  not  appreciably  altered. 
Moraczewski3  and  others  have  found  an  abnormal  retention  of 
calcium  and  phosphorus. 


Table  XI. 
N.  H.  Female,  mt.  30  Years.    Case  op  Acromegaly.    Examination  of  Urinte. 


<3 

a 

a 
'■3 

a 

CD 

M 

60 

O 

Date. 

•p 
'3 

a 

p 

k 

X 

^ 

5 

o 
o° 

s 

5 

o 
eg 

0> 

o 
a. 

O 

i 

- 
£ 
a 

£ 

L4 

& 
-1 

- 

C 

o 

a 
o 

a 

§ 

g 

cj 

o 

a 

a 
"3 

S 

M 

m 

< 

— 

""i 

f. 

H 

H 

< 

< 

grms. 

grms. 

o 

c.c. 

grms. 

grms. 

grms. 

% 

% 

28.1.15 

acid 

1016 

— 

— 





0-78 

1-69 

0-064 

8-1 

034 

0-17 

0016 

29.1.15 

acid 

1010 

— 

— 



0-49 

113 

0-039 

7-3 

0-38 

0-188 

0  013 

30.1.15 

acid 

1015 

— 

— 



0-714 

0071 

0-10 

0-4 

0-288 

00145 

1.2.15 

acid 

1015 

— 

— 



0-77 

0-059 

7-7 

0-3 

0-318 

0-0017 

2.2.15 

acid 

1012 



063 

0-05 

8-0 

032 

0-212 

0-0095 

3.2.154 

513 

neutral 

1012 



0-448 

0-04 

9  0 

0  45 

0161 

0  0052 

12.2.15 

1311 

acid 

1013 



0-462 

1-75 

0067 

145 

037 

0-26 

0-0004 

13.2.15 

1625 

acid 

1012 



0-742 

1-22 

0061 

8-3 

0-3 

015 

0-032 

15.2.15 

1083 

acid 

1015 



0-84 

1-75 

0-061 

7  3 

0-35 

0-34 

00227 

Hi.  2. 15 

acid 

1013 



0-644 

111 

005 

7-8 

0-41 

0-22 

0-0088 

17.2.15 

1311 

acid 

1012 

0-826 

1-75 

0  05 

61 

0-4 

0-24 

0-0005 

L8.2.15 

1254 

acid 

1014 

0-812 

1-72 

0047 

5-8 

0-3 

0-33 

0  001 

19.2.15 

1311 

acid 

1015 

0-700 

1-41 

0  049 

7-0 

0-25 

0-2! 

0001 

20.2.15 

1311 

acid 

1011 





0-559 

1-19 

0-35 

0-23 

0003 

22.2.15 

1454 

acid 

1020 





0-729 

1-55 

0-07 

!>-i; 

0-5 

0-18 

00015 

23.2.15 

1340 

acid 

1015 





0-491 

1061 

0-05 

10-0 

0-6 

017 

00015 

24.2.15 

1(553 

acid 

1010 





043 

10 

0-04 

8-6 

0-26 

0-21 

0  0002 

I  have  examined  the  urinary  excretions  of  two  cases  of  acro- 
megaly with  the  patients  on  a  full  mixed  diet.  Tables  XI  and 
XII  show  the  results  obtained. 

1  Franchini,  G.,  Riv.  Speriment.  di  Freniat,  1907,  xxxiii,  888  ;  and  Berl.  Klin. 
Woch.,  1908,  xlv,  1636. 

2  Franchini,  G.,  and  G.  J.  Giglioli,  Nouvelle  Icon,  de  la  Salpetriere,  1908,  xxi,  325. 

3  Moraczewski,  W.  D.  von,  Zeit.f.  Klin.  Med.,  1901,  xliii,  336. 

4  Decompression  operation:  February  3,  1915.     Calcium  index  in  blood,  1*05. 

February  16,  1915.     Calcium  index  in  blood,  0*54. 


230     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 


It  will  be  seen  that  there  is  no  definite  abnormality  to  be 
discovered,  except  in  regard  to  the  calcium  metabolism.  The 
excretion  of  this  substance  was  very  variable  and  below  normal 
except  on  a  few  occasions,  when  large  quantities  were  excreted. 

Table  XII. 
G.  J.  Male,  mt.  27  Years.    Case  of  Acromegaly.    Examination  op  Urine. 


a 

ea 

a 

a     ! 

fc 

3 

g 

P 

O 

H 

0) 

ft 

■6 
'3 

5 

o 

CO 

a 

43 

'o 

Date. 

>> 

a 

«s 

c 

£ 

CS 

o^ 

33 

"5 

c3 

s 

.2 

"8 

a 

S3 

z 

~ 

'■5 
<s 
o 

1 

— 

"3 

o 

o 

M 

"a 
o 
S 

2 

e3 

3 

53 

cT 

a 

'3 
"3 

<y 

ti 

m 

< 

P 

< 

m 

H 
grms. 

H 

< 
grnis. 

< 

grms. 

pT 

o 

c.c. 

grms. 

% 

grins. 

%     i 

17.2.151 

acid 

1025 

— 

— 

L-62 

345 

05 

0-46 

00061 

18.2.15 

acid 

1011 

— 

— 

0-644 

1-37 

0-072 

11  3 

0-4 

016 

0-0064J 

19.2.15 

1197 

acid 

1006 

— 

— 

0-98 

21 

0-056 

5  6 

0-08 

0-088 

0-0006 

20.2.15 

1223 

acid 

1019 

— 

— 

1-75 

3-72 

0-34 

0-26 

0-0005 

22.2.15 

1254 

acid 

1019 

— 

— 

1-72 

3-66 

111 

6-4 

0-55 

0-209 

0-0044 

23.2.15 

1484 

acid 

1012 

— 

— 

112 

233 

0  055 

5  0 

0-23 

0109 

0-035 

24.2.15 

1140 

acid 

1012 

— 

— 

1-08 

2-32 

0072 

6-6 

0-2 

0-259 

0-004 

25.2.15 

1111 

acid 

1017 

— 

— 

0-99 

2-1 

0-106 

10-7 

0-349 

0-289 

0-01 

26.2.18 

1254 

acid 

1015 

— 

— 

111 

2  54 

112 

0-606 

0-24 

0-22 

0-0022 

27.2.15 

1340 

acid 

1011 

— 

— 

1-3 

2  74 

0084 

6-4 

0-17 

1-4 

0013 

2.3.15 

1454 

acid 

1010 

— 

r 

0-63 

1-3 

0-53 

8-3 

0-29 

0-094 

0-0004 

The  pathology  of  acromegaly. — Before  describing  the  more 
exact  observations  which  have  been  made  concerning  the  patho- 
logical histology,  I  must  refer  to  an  interesting  theory,  recently 
revived  by  Keith2,  namely,  that  acromegaly  may  represent  an 
atavistic  tendency,  since  the  acromegalic  skull  resembles  in  its 
prognathism  the  skull  of  primitive  Man  and  of  the  higher  apes. 
I  am  not  aware  that  any  histological  evidence  has  been  adduced 
to  support  this  theory,  although  I  have  found  that  there  is  nor- 
mally a  greater  degree  of  chromophobia  in  the  pars  anterior  in 
some  of  the  lower  orders  of  mammals,  such  as  the  rodents, 
than  in  the  higher. 

The  histological  pathology  of  acromegaly  has  been  carefully 
investigated  by  Benda3,  Fischer4,  Gushing5  and  many  others. 

1  Calcium  index  in  blood,  0-4. 

2  Keith,  A.,  Lancet,  1911,  i,  993. 

3  Benda,  C,  Berl.  Klin.  Woch.,  1900,  xxxvii,  1005  ;  Handbuch  d.  Pathol.  Anat. 
d.  N  ervensystem,  1904,  ii,  1418. 

4  Fischer,  B.,  Hyjmphysis,  Ahromegalie  und  Fcttsucht,  Wiesbaden,  1910. 

5  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


ACROMEGALY  231 

The  disease  is  almost  always  accompanied  by  considerable 
hypertrophy  of  the  pars  anterior  (fig.  151),  and  an  enlargement 
of  the  sella  turcica  which  can  be  demonstrated  by  X-rays.  Occa- 
sionally, however,  no  definite  enlargement  has   been  found1,2. 

Benda  has  shown  that  the  histological  changes  in  the 
anterior  lobe  may  consist  of  so  considerable  an  increase  of  the 
eosinophil  cells  that  the  whole  gland  appears  to  consist  of  this 
one  type  of  cell.  He  has  also  found  that  these  cells  often  assume 
an  adenomatous  arrangement.  Benda  could  find  no  record  in 
the  literature  of  any  tumour  other  than  an  adenoma — presumably 
innocent  or  malignant — being  associated  with  acromegaly. 
Benda3,  Lowenstein4,  Fischer5,  and  Gushing6  believe  that  many 
cases  of  hyperplasia  have  been  taken  for  sarcomata  and  peri- 
theliomata,  owing  to  the  rapidity  of  proliferation  and  the  diffi- 


Fig.  151. 

The  normal  pituitary  (a)  shown  for  comparison  iti  regard  to  size  with  the 
pituitary  in  a  case  of  acromegaly  (b).  {From  a  'photograph  kindly  lent  by  the 
Medical  Superintendent  of  Whittingham  Asylum.) 

Xl 

culty  of  recognizing  the  different  stages  in  the  development  of 
the  cells. 

Cagnetto7  has  reported  a  case  of  sarcoma  of  the  pituitary 
in  a  girl  aged  9,  which  was  not  associated  with  acromegaly  ;  and 
Rennie8  a  case  of  endothelioma  in  a  boy,  16  years  of  age,  in 
which  there  was  some  degree  of  infantilism.  It  is  probable  that 
usually  in  these  circumstances  the  secretory  cells  of  the  pituitary 
are  destroyed.     Fischer5,  moreover,  states   that  tuberculous  and 

1  Lewis,  D.,  Bull.  Johns  Hopk.  Hosp.,  1905,  xvi,  157. 
-  Linsmayer,  L.,  Wien.  Klin.  Wuch.,  1894,  vii,  294. 

3  Benda,  C,  Berl.  Klin.  Woch.,  1900,  xxxvii,  1005  ;  Handbuch  d.  Pathol.  Anal, 
d.  Nervensystem,  1904,  ii,  1418. 

4  Lowenstein,  C,  Virchow's  Arch.,  1907,  clxxxviii,  44. 

5  Fischer,  B.,  Hypophysis,  Akromegalie  mid  Fettsucht,  Wiesbaden,  1910. 

6  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

7  Cagnetto,  G.,  Virchow's  Arch.,  1907,  clxxxviii,  197. 

8  Rennie,  G.  E.,  Brit.  Med.  Journ.,  1912,  i,  1355. 


232     DISORDERS   ASSOCIATED   WITH    THE   PITUITARY 

syphilitic  lesions  of  the  hypophysis  do  not  cause  acromegaly. 
In  these  circumstances,  also,  the  lesions  would  be  destructive 
and  not  hyperplastic  in  character. 

Cagnetto1,  Sternberg2  and  Fischer3  believe  that  adenocar- 
cinoma of  the  pars  anterior  may  produce  acromegalic  symptoms. 
Fischer  in  discussing  the  question  remarks  that  there  is  great 
individuality  with  regard  to  the  metastases  of  various  malig- 
nant tumours  :  sometimes  metastases  will  produce  secretion, 
and  at  other  times  they  will  not.  It  is  for  this  reason  he  believes 
that  some  malignant  tumours  of  the  pituitary  cause  acromegaly, 
while  others  do  not.     I  shall  refer  to  this  subject  later  (p.  269). 

Furnivall4  collected  results  of  post-mortem  examinations 
performed  upon  49  cases  of  acromegaly  by  many  different 
pathologists.  Of  this  number  11  were  stated  to  be  due  to 
sarcomata,  7  to  simple  hypertrophy,  6  to  adenomata  and  9  to 
'tumours'  of  the  hypophysis.  Rolleston,  also,  has  recorded  a 
case  of  sarcoma  of  the  pituitary,  which  invaded  the  brain  and 
petrous  bone.  It  is  probable,  however,  that  hyperplasia  of  the 
hypophysis  has  frequently  been  mistaken  for  sarcoma. 

It  has  often  been  argued  that  some  of  the  symptoms  of 
acromegaly  may  be  due  to  interference  with  the  function  of  the 
posterior  lobe.  This  is  probably  true  in  regard  to  glycosuria  which, 
when  present,  may  be  secondary  either  to  injury  (by  compression) 
of  the  pars  posterior,  or  to  hyperplasia  of  the  pars  intermedia. 
Nevertheless,  in  this  connexion  it  is  important  to  remember  that 
acromegaly  has  been  known  to  exist  without  enlargement  of  the 
hypophysis5,6.  Such  a  condition  is  probably  comparable  with 
cases  of  hyperthyroidism,  without  enlargement  of  the  thyroid. 

In  discussing  the  pathology  of  acromegaly  Cushing7  reports 
cases  diagnosed  clinically  as  hyperhypophysism,  which  on  post- 
mortem examination  revealed  in  most  instances  a  '  strumous  ' 
condition — -that  is,  hyperplasia  either  of  the  eosinophil  or  more 
rarely  of  the  chromophobe  cells.  In  a  very  few  there  was 
cystic  or  necrotic  degeneration   in   the  pars  anterior.       Fischer3 

1  Cagnetto,  G.,  Virchoiv's  Arch.,  1907,  clxxxviii,  197. 

2  Sternberg,  M.,  Zeit.f.  Klin.  Med.,  1895,  xxvii,  86. 

3  Fischer,  B.,  Hypophysis,  Alcromegalie  und  Fettsucht,  Wiesbaden,  1910. 

4  Furnivall,  P.,  Trans.  Path.  Soc,  1898,  xlix,  204. 

5  Lewis,  T>.,  Bull.  Johns  Hopk.  Hosp.,  1905,  xvi,  157. 

6  Linsmayer,  L.,  Wien.  Klin.  Woch.,  1894,  vii,  294. 

7  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


ACROMEGALY  233 

asserts    that    eosinophil    adenoma    is    the    hall-mark    of     acro- 
megaly. 

It  appears,  therefore,  that  the  symptoms  of  the  disease 
known  as  acromegaly  are  primarily  dependent  on  an  excessive 
secretion  of  the  eosinophil  or  the  active  chromophobe  cells 
of  the  anterior  lobe  (fig.  152).  This  is  in  keeping  with  the 
explanation  already  given  of  the  secretory  functions  of  the  cells 
of  the  pars  anterior. 

^•1.  «...  °%°8se/  •?■»*•%**'.     °'i%    '*■ 

'.« r  fc*-^  .  iv^^v^iv  •£ 


Fig.  152. 

Section  of  a  portion  of  the  pars  anterior  removed  at  operation  (by  W.  Theltvall 
Thomas)  from  a  case  of  acromegaly,  showing  an  adenomatous  arrangement  of 
chromophobe  cells.  There  is  much  blood  scattered  through  the  section — probably 
the  result  of  surgical  interference. 

X  150. 

Although  in  these  circumstances  there  is  always  at  first  a 
condition  of  hyperplasia  present  in  the  pars  anterior,  it  is  pro- 
bable that  the  main  features  of  acromegaly  exist  for  some  time 
after  the  anterior  lobe  has  ceased  to  be  excessively  active. 
Further,  it  has  rightly  been  emphasized  by  Cushing  that  hypo- 
pituitarism very  frequently  succeeds  hyperpituitarism,  and  that 
it  is  not  uncommon  to  find  in  this  later  stage  a  cystic  or 
necrotic  change  present  in  the  anterior  lobe. 


234     DISORDERS   ASSOCIATED   WITH    THE    PITUITARY 

Before  leaving  the  discussion  of  the  pathology  of  acromegaly 
and  the  question  of  the  actual  situation  of  the  lesion  in  the 
pituitary  body,  it  is  necessary  briefly  to  refer  to  the  interesting 
fact  that  acromegaly  may  be  caused  by  hyperplasia  in  an  acces- 
sory anterior  lobe  ;  that  is  to  say,  hyperplasia  may  occur  in  a 
congenital  inclusion  of  the  hypophysis  in  the  track  of  the  cranio- 
pharyngeal  canal  through  the  sphenoid  bone.  These  inclusions 
of  a  portion  of  Rathke's  pouch  are  probably  not  rare,  but  only 
a  few  cases  are  known  in  which  acromegaly  has  arisen  from  such 
rests.  Erdheim1  has  recorded  such  a  case.  He  found  an 
eosinophil  hypophysial  tumour,  extending  into  the  sphenoidal 
cells  below  the  sella  turcica,  which  had  been  associated  with 
the  symptoms  of  acromegaly.  The  pituitary  body  proper  was 
quite  normal. 

The  following  question  now  arises  :  How  far  are  pathological 
lesions  in  the  pituitary  responsible  for  the  clinical  manifesta- 
tions associated  with  acromegaly  ? 

Tandler  and  Grosz2  considered  that  hyperplasia  and  event- 
ually hypoplasia  in  the  pituitary  were  secondary  to  primary 
genital  atrophy.  This  assumption  was  partly  based  on  experi- 
mental evidence  ;  but  it  in  no  way  accords  with  the  clinical 
facts,  for  genital  hypoplasia  folloAvs,  rather  than  precedes,  the 
onset  of  acromegaly,  and  undergoes  remissions  when  improve- 
ments occur  in  the  course  of  the  disease. 

In  most  cases  there  is  no  doubt  that  while  in  this  disease  the 
primary  pathological  lesion  is  in  the  epithelial  portions  of  the 
pituitary  and  most  of  the  clinical  manifestations  are  the  result 
thereof,  yet  in  their  entirety  the  clinical  phenomena  form  a 
pluriglandular  syndrome.  This,  indeed,  is  the  only  explanation 
that  can  be  offered  in  some  anomalous  cases. 

Many  recent  observers  have  recognized  changes  in  the  other 
hormonopoietic  organs  in  acromegaly ;  but  if  we  except  tentative 
discussions  by  Biedl3  and  Cushing4,  and  the  work  of  Claude  and 
Gougerot5  on  somewhat  similar  lines,  it  does  not  appear  to  have 
been  seriously  put  forward  that  primary  disease  of  an  organ  of 

1  Erdheim,  J.,  Beitr.  z.  Pathol.  Anat.  u.  z.  Allg.  Pathol,  1909,  xlvi,  233. 

2  Tandler,  J.,  and  S.  Grosz,  Wien.  Klin.  Woch.,  1907,  xx,  1596. 

3  Biedl,  A.,  Innere  Selcretion,  2nd  ed.,  1913. 

4  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

5  Claude,  H.,  and  H.  Gougerot,  Joum.  de  Physiol,  et  de  Pathol.  Gen.,  1908,  x, 
469  and  505. 


ACROMEGALY  235 

internal  secretion  does  not  produce  symptoms  entirely  dependent 
upon  that  lesion,  but  rather  upon  a  pluriglandular  involve- 
ment. It  is,  for  example,  not  impossible  that  hyperthyroidism — 
apparently  a  pathological  entity — is  dependent  partly  on  the 
withdrawal  of  the  restraining  influence  of  other  internal  secretions. 
The  way  for  this  point  of  view  has  been  prepared  by  our 
consideration  of  the  physiological  interrelations  between  the 
pituitary  and  the  other  organs  of  internal  secretion ;  but  in 
order  to  view  the  whole  subject  more  completely  I  shall  first 
consider  the  pathological  condition  known  as  'hypopituitarism'. 


HYPOPITUITARISM 

Incidence  and  symptoms. — It  is  possible  that  hypopituitar- 
ism may  exist  as  a  congenital  lesion,  but  such  a  state  of 
affairs  is  difficult  to  determine,  for  it  is  not  until  the  child  is 
growing  up  that  the  signs  of  this  lesion  become  recognizable. 

Hypopituitarism  occurring  before  puberty  gives  rise  to  three 
distinct  conditions  :  (a)  infantilism  somatic  and  sexual,  with- 
out adiposity  (Lorain  type)  ;  (b)  stunted  growth  with  sexual 
infantilism  and  adiposity  ;  (c)  overgrowth  with  some  adiposity 
and  genital  inactivity. 

Levi1  was  probably  the  first  to  direct  attention  to  infan- 
tilism (Lorain  type)  due  to  pituitary  lesions. 

This  type  of  case  is  attributed  by  Gushing2  and  others  to 
insufficiency  in  the  secretion  of  the  pars  anterior  ;  and  in  his 
case  (iv)  there  was  an  enlargement  of  the  sella  turcica. 

I  have  seen  a  case  in  which  a  girl  at  the  age  of  18  years 
resembled  a  child  of  10  years  of  age  (fig.  153),  and  in  whom  there 
was  a  shallow  sella  turcica  (fig.  154). 

Rennic3,  also,  has  recorded  an  interesting  case  of  this  type 
of  infantilism  in  a  boy  suffering  with  an  endothelioma  of  the 
pituitary. 

It  seems  probable  that  in  those  cases  in  which  the  sella 
turcica  is  small  the  condition  has  existed  ab  initio  ;  while  in 
those  in  which  the  sella  is  distorted  and  large  there  has  been 
some  postnatal  and  preadolcscent  destruction  of  the  pars 
anterior  without  injury  to  the  pars  posterior.  It  is  probable, 
also,  that  when  there  is  a  preadolcscent  lesion  of  the  pituitary 
producing  adiposity,  stunted  growth  and  sexual  infantilism,  the 
whole  organ  is  affected. 

Since  the  condition  of  dystrophia  adiposogenitalis  was  first 
described  by  Frohlich4  in  the  case  of  a  boy,  14  years  of  age,  a 

1  Levi,  E..  Nouv.  Icon,  de  la  Salpetriere,  1908,  xxi,  297  and  421. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

3  Rennie,  G.  E.,  Brit.  Med.  Joum.,  1912,  i,  1355. 

4  Frohlich,  A.,  Wien.  Klin.  Bundsch.,  1901,  xv,  883. 


HYPOPITUITARISM   BEFORE   PUBERTY  237 


Pio.  153. 

Photograph  of  a  girl,  aged  18  years,  showing  general  infantilism  due  to  under- 
development of  the  pituitary.  The  patient  measured  4  ft.  3  ins.  in  height  and 
weighed  4  stones  3  lbs. 


238     DISORDERS   ASSOCIATED   WITH   THE    PITUITARY 

number  of  cases  of  this  state  of  affairs  is  on  record1,2 — so  many 
that  it  is  impossible  to  give  all  the  references. 

One  of  the  most  interesting  cases  is  that  of  Madelung3  in 
which  a  girl  9  years  of  age  was  shot  with  a  rifle-bullet  which 
lodged  in  the  sella  turcica.  The  child  developed  the  typical 
symptoms  of  this  syndrome,  but  these  were  not  recognized  as 
such  when  the  case  was  reported. 

Most  of  the  cases,  however,  have  been  due  to  neoplasms  or 
cystic  formations  in  the  pars  anterior. 


Fig.   154. 


Radiograph  of  the  sella  turcica  in  the  case  of  ateliosis  illustrated  in  figure  146. 
(By  Thurston  Holland.) 

X}. 

The  syndrome,  dystrophia  adiposogcnitalis,  is  easily  recog- 
nized (fig.  155).  I  shall  discuss  it  in  detail  presently  ;  but  one 
point  must  be  mentioned  here.  In  boys  the  skeleton  tends  to 
develop  on  feminine  lines,  for  the  bones  are  light  and  the  ex- 
tremities tapering. 

The  third  group  of  preadolescent  cases  of  hypopituitarism, 
in  which  there  is  some  skeletal  overgrowth  with  adiposity  and 
genital  inactivity,  has  been  described  by  Neurath4  and  dishing1. 
Cushing  interprets  the  phenomena  seen  as  being  dependent  on 

1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Special  discussion,  Proc.  Roy.  Soc.  Med.  (Neiirol.  and  Ophthalmol.  Sects.), 
1913,  vi,  i. 

3  Madelung,  0.,  Virhandl.  d.  Deutsch.  Gesellsch.f.  Chir.,  1904,  xxxiii,  164. 

4  Neurath,  R.,  Wien.  Klin.  Woch.,  1911,  xxiv,  43. 


HYPOPITUITARISM   BEFORE    PUBERTY  239 

excessive  secretion  from,  the  pars  anterior  with  diminished  pars 
posterior  secretion.  But  this  certainly  does  not  explain  the 
genital  infantilism  in  the  case  of  males.  Neurath,  however, 
considers  it  possible  that  the  whole  train  of  symptoms  is  due 
to  primary  lesions  in  the  gonads  producing  a  condition  of  re- 
sembling eunuchism.  But  neither  of  these  explanations  quite 
accounts  for  the  features  of  the  following  case. 


Fig.  155. 

Three  views  of  a  boy,  aged  16  years,  suffering  with  dystrophia  adiposogenitalis. 
He  measured  4  ft,  6  ins.  in  height  and  weighed  7  st.  9  lbs.  There  was  a  carbo- 
hydrate-tolerance of  over  300  grammes  of  sugar.      (Photograph.)     (F.  E.  Batten.) 

This  patient  came  under  observation  at  the  age  of  18-|  years, 
being  referred  to  me  by  her  father  who  is  a  doctor.  Her  only 
complaint  was  that  she  had  not  menstruated.  On  examination 
the  uterus  was  found  to  be  infantile — rudimentary,  I  thought  at 
the  time. 

A  radiograph  of  the  sella  turcica  showed  this  fossa  to  be  re- 
markably small  (fig.  15G).  When  first  seen  the  patient  was  a 
bright,    handsome,    finely    developed    girl    measuring    5    feet    8| 


240     DISORDERS   ASSOCIATED  WITH  THE   PITUITARY 

inches  in  height,  and  weighing  11  stones  2  pounds.  The  carbo- 
hydrate-tolerance was  over  350  grammes  of  dextrose — that  is 
to  say,  no  sugar  appeared  in  the  urine  after  this  amount  had  been 
consumed,  and  it  was  impossible  for  the  patient  to  take  more. 

Two  years  later  her  father  wrote  to  say  that  she  weighed 
15  stones  4  pounds  in  spite  of  the  administration  of  whole-gland 
pituitary  extract.  After  that  time  the  administration  of  pituit- 
ary extract  was  discontinued. 


Fig.  156. 

Radiograph    of   the  human  sella  turcica   in  a  case  of  underdevelopment  of  the 
pituitary  associated  with  an  infantile  uterus.     (By  Thurston  Holland.) 

Recently,  at  the  age  of  23  years,  the  patient  has  commenced 
menstruating  regularly.  It  is  this  last  fact  which  almost  places 
the  case  in  a  category  of  its  own. 

After  puberty  there  may  be,  as  in  hyperpituitarism,  many 
stages  and  phases  of  hypopituitarism  ;  but,  as  is  so  frequently 
the  case  in  newly  described  conditions,  only  the  most  pronounced 


HYPOPITUITARISM   AFTER   PUBERTY 


241 


types    are    generally   recognized,   while    the    less    severe    lesions 
with  slight  clinical  manifestations  escape  adequate  recognition. 

The  milder  forms  of  hypopituitarism  are  undoubtedly  much 
commoner  than  is  generally  supposed.  The  patients  are  usually 
of  the  female  sex  between  25  and  35  years  of  age.  The  most 
prominent  symptoms  are  increasing  obesity,  lassitude  and 
amenorrhcea.  Advice  is  usually  sought  for  the  menstrual  sup- 
pression. At  first  the  amenorrhcea  alternates  with  irregular 
and  scanty  menstruation,  and  finally  this  function  ceases. 

Most  text-books  of  gynaecology  describe  obesity  as  a 
primary  cause  of  amenorrhoea  and  sterility.  That  it  may  be  is 
probable1  ;  but  it  appears  likely  that 
in  many  cases  the  obesity  is  really  due 
to  pituitary  insufficiency.  I  have  seen 
atrophy  of  the  uterus  from  this  cause  in 
a  woman  of  36  years  of  age.  Up  to  30 
years  of  age  her  menses  had  been  regular. 

In  the  adult,  as  in  the  child,  the  more 
serious  states  of  hypopituitarism — produced 
by  cysts,  neoplasms  or  traumatic  lesions — 
form  the  definite  syndrome  dystrophia 
adiposogenitalis.  In  this  condition  the 
subject  becomes  obese  ;  and  the  male 
assumes  a  feminine  configuration  (feminine 
type)  (fig.  157).  In  the  female  men- 
struation ceases  ;  in  the  male  there  is 
impotence  ;  and  the  genital  organs  of  both 
sexes  eventually  atrophy.  The  blood- 
pressure  is  low  and  the  temperature  sub- 
normal. There  is,  also,  so  great  an  increase 
in  the  carbohydrate-tolerance  with  hypo- 
glycaemia,  that  the  ingestion  of  more  than 
500  grammes  of  dextrose  may  be  required 
to  produce  glycosuria.  The  sugar-tolerance 
may  be  reduced  and  the  blood-pressure 
raised  by  the  injection  of  an  extract  of  the 
posterior  lobe,  while  the  temperature  maybe  Parsons.) 
elevated  by  anterior  lobe  extract  ('thermic  reaction'  of  Gushing). 

In  the  more  severe  and  progressive  types  of   the  disease  the 
1  Marshall,  P.  H.  A.,  Sci.  Progress,  1908,  ii,  369. 

16 


Case  of  dystrophia  adip- 
osogenitalis   in    a     man, 

showing  a  tendency  to 
feminine  contour  (typus 
f<  mi  n't  mi).  {Photograph.) 
[Grainger      Stewart     and 


242     DISORDERS   ASSOCIATED  WITH   THE    PITUITARY 


20m.m  white  & 

Colours 


Shaded'  scotoma  Reo* 


Fig.  158. 

Fields  of  vision  in  a  case  of  dystrophia  adiposogenitalis,  showing  bitemporal 
hemianopia,  and  disappearance  of  the  colour-fields  before  the  white.  (Bishop 
Harman.) 


Fig.  159. 

Left  fields  of  vision  in  the  case  of  dystrophia  adiposogenitalis  shown  in  figure  157, 
showing  gradual  progression  towards  blindness:  A,  on  May  10,  1911;  b,  on 
Feb.  12,  1913.     (Grainger  Stewart  and  Parsons.) 


HYPOPITUITARISM   AFTER    PUBERTY 


243 


increasing  size  of  the  tumour  raises  the  intracranial  tension, 
causing  severe  headaches,  and  by  injury  to  the  optic  tract 
gives  rise  to  hemianopia — colour-vision  disappearing  before  the 
white  field  (fig.  158) — sometimes  diplopia,  and  eventually  almost 
complete  blindness  (fig.  159).  In  these  circumstances  the  sella 
turcica  is  usually  greatly  enlarged,  and  often  the  posterior  clinoid 
processes  are  completely  eroded  (fig.  160).  The  deformation  of 
the  sella  is  usually  greater  in  dystrophia  adiposogenitalis  than 
in  acromegaly.     Vomiting  is  very  rare  in  these  cases. 


Fig.  160. 

Radiograph  of  the  sella  turcica  in  a  case  of  dystrophia  adiposogenitalis, 
showing  disappearance  of  the  posterior  clinoid  processes.  The  fields  of  vision  of 
this  case  are  shown  in  figure  158.     (Bishop  Harman.) 


Psychical  disturbances  may  be  present  as  the  result  of  pres- 
sure on  the  frontal  lobes  ;  and  a  specific  hypophysial  psychosis, 
due,  it  is  supposed,  to  perverted  pituitary  secretion,  has  been 
described.  The  subjects  may,  however,  show  all  degrees  of 
cerebral  disturbance  from  a  torpidity  or  irritability  to  advanced 
forms  of  epilepsy  and  insanity. 

The  relationship  of  epileptiform  seizures  to  lesions  producing 
hypopituitarism  has  been  studied  by  dishing1. 

There  appears  to  be  no  doubt  that,  with  a  pituitary  lesion 

1  Cashing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


244     DISORDERS   ASSOCIATED  WITH   THE   PITUITARY 

extending  upwards  into  the  interpeduncular  region,  pressure 
on,  or  irritation  of,  the  uncinate  gyrus  may  be  produced.  In 
these  circumstances  attacks  of  loss  of  memory,  or  even  '  fits  ' 
preceded  by  gustatory  or  olfactory  phenomena,  occur.  These 
manifestations,  with  general  epileptiform  seizures,  appear  occa- 
sionally to  follow  pituitary  insufficiency  apart  from  pressure  on 
the  gyrus,  and  are  probably  due  to  increased  cortical  irritability. 
The  skin  of  patients  with  hypopituitarism  differs  from  that 
of  patients  suffering  with  acromegaly  :  in  the  former  condition 
the  integument  is  soft  and  smooth,  the  hair  tends  to  fall  out, 
and,  unless  the  condition  be  a  sequel  to  acromegaly,  the  extremi- 
ties are  usually  delicate  and  tapering. 

The  pathology  of  hypopituitarism. — As  we  have  seen  in 
certain  preadolescent  types,  the  lesion  of  the  pituitary  may  be 
congenital ;    but  of  this  we  have  no  certain  knowledge. 

Until  quite  recently  it  had  been  accepted  by  nearly  all  who 
have  inquired  into  the  subject  that  hypopituitarism  is,  strictly 
speaking,  hypohypophysism — that  is  to  say,  insufficiency  of  the 
partes  anterior  and  intermedia.  In  order  to  discuss  this  question 
we  shall  be  obliged  to  reconsider  the  relative  positions  occupied  by 
the  anterior  and  posterior  lobes,  including  the  pars  intermedia. 

The  experimental  work  of  Paulesco1,  of  dishing2  and  his 
colleagues,  and  of  Biedl3  appeared  to  place  beyond  all  doubt 
the  fact,  as  emphasized  by  them  in  their  respective  publications, 
that  in  dogs  dystrophia  adiposogenitalis  is  always  produced  by 
partial  extirpation  of  the  anterior  lobe,  and  that  removal  of 
the  posterior  lobe  causes  no  symptoms.  Yet  we  find  that  Cushing 
who  has  done  the  most  experimental  work  on  this  subject,  and 
was  apparently  certain  of  his  results  and  conclusions,  in  his 
clinical  exposition4  states  that  the  condition  of  hypopituitarism 
is  due  to  posterior  lobe  insufficiency.  This  view  has  also  been 
advanced  by  Fischer5,  apparently  on  pathological  grounds. 

The  reason  why  Cushing  changed  his  views  appears  to  have 
been  partly  because  of  post-mortem  findings,  and  partly  because 

1  Paulesco,  N.  C,  Lliypophyse  du  cerveau,  Paris,  1908. 

2  Crowe,  S.  J.,  H.  Cushing,  and  J.  Homans,  Bull.  Johns  Hoph.  Hosp.,  1910, 
xxi,  127. 

3  Biedl,  A.,  Inncre  Sekretion,  2nd  ed.,  1913. 

4  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

5  Fischer,  B.,  Hypophysis,  Akromegalie  und  Fcttsucht,  Wiesbaden,  1910. 


HYPOPITUITARISM   AFTER   PUBERTY  245 

injections  of  the  extract  of  the  posterior  lobe  lessen  some  of  the 
symptoms  associated  with  hypopituitarism,  such  as  the  carbohy- 
drate-tolerance and  the  low  blood-pressure.  On  the  other  hand, 
he  himself  pointed  out  that  the  subnormal  temperature  found  with 
hypopituitarism  is  raised  by  extract  of  the  anterior  lobe  ('thermic 
reaction  '),  and  not  by  infundibulin.  Apart  from  the  effects 
produced  by  the  extract  of  the  posterior  lobe  in  hypopituitarism, 
dishing  adduces  other  clinical  evidence  which,  he  considers, 
confirms  his  latest  conclusions.  He  states  that  an  internal 
hydrocephalus  may  produce  insufficiency  of  the  secretion  ot  the 
posterior  lobe,  and  at  the  same  time  "  may  apparently  either 
stimulate  or  inhibit  the  anterior  lobe "  1.  But  the  fact  that 
the  pars  nervosa  of  the  pituitary  in  man  is  not  hollow,  as  it  is  in 
some  of  the  lower  animals,  and  cannot,  therefore,  be  distended 
by  intraventricular  tension  appears  to  have  been  overlooked  by 
Gushing.  Any  pressure  that  may  be  produced  by  hydrocephalus 
in  Man  must  affect  equally  both  lobes. 

This  observer,  therefore,  introduces  a  fresh  syndrome  : 
namely,  a  condition  of  adiposity  with  sexual  precocity  or 
excitation.  Further,  this  syndrome  may  be  associated,  he  says, 
with  skeletal  undergrowth  or  overgrowth.  Cases  are  cited,  it 
must  be  admitted,  from  his  exceptional  experience  to  illustrate 
these  phenomena  ;  but  whether  a  correct  interpretation  has 
been  placed  on  them  is  open  to  argument. 

With  regard  to  Cushing's  experiments  and  those  of  Biedl, 
I  have  demonstrated  that  it  is  possible  to  remove  large  or 
small  quantities  of  the  anterior  lobe  and  so  to  bring  about  in- 
sufficiency in  this  structure,  as  is  shown  by  the  genital  atrophy 
which  subsequently  occurs,  without  in  any  single  case  producing 
the  syndrome  dystrophia  adiposogenitalis  by  this  procedure. 
Further,  it  has  been  proved  that  removal  of  the  whole  or  a 
portion  of  the  posterior  lobe  causes  neither  genital  atrophy 
nor  carbohydrate-tolerance.  The  only  way  in  which  I  was  able 
to  produce  dystrophia  adiposogenitalis  was  by  separating  or 
clamping  the  stalk. 

These    results,     read     in     conjunction     with     the     foregoing 
views    of    Cushing,    serve    to    illustrate    the    uncertainty  of    our 
knowledge  or  at  any  rate  the  conflicting  nature  of  the  experi- 
mental evidence  at  our  disposal  for  interpretation  into  the  terms 
1  Cushing,  H.,  Tin  Pituitary  Body  and  Us  Disorders,  1912. 


246     DISORDERS   ASSOCIATED   WITH  THE  PITUITARY 

of  clinical  phenomena.  Fischer1,  without  any  experimental 
data  of  his  own  to  support  him  and  arguing  from  a  pathological 
standpoint,  asserts  that  dystrophia  adiposogenitalis  is  due  to 
lesions  of  the  posterior  lobe.  My  experimental  results  show  that 
interference  with  the  stalk  is  the  only  lesion  which  gives  rise  to 
this  condition. 

Erdheim2  has  shown  that  not  infrequently  in  dystrophia 
adiposogenitalis  aggregations  of  squamous  or  columnar  epi- 
thelium are  found  in  the  neighbourhood  of  the  cleft.  These 
are  either  embryonic  rests  or  metaplasias,  and  from  them 
growths  and  cysts  may  arise.  Seven  cases  have  been  described 
by  Erdheim,  and  similar  tumours  have  been  recorded  by  others. 
Cushing3,  in  an  interesting  discussion  of  the  subject,  mentions 
a  case  of  a  tumour  arising  in  the  upper  part  of  the  cleft,  and 
he  illustrates  the  histological  appearances  which  resemble  those 
of  thyroid  tissue.  It  is  doubtful,  however,  whether  large  aggre- 
gations of  colloid-containing  acini  in  the  pars  intermedia  of  the 
human  subject  can  be  considered  neoplastic.  I  have  seen  this 
condition  well  marked  in  pregnancy,  and  in  other  conditions. 
Possibly  this  state  of  affairs  is  pathological  in  so  far  as  the 
amount  of  colloid  and  the  extent  of  the  acinous  formation  of  the 
cells  are  concerned,  but  it  does  not  usually  constitute  neoplasia. 

When  there  is  a  definite  tumour  in  the  neighbourhood  it 
may  cause  compression  of  the  pituitary  and  interfere  with  its 
function  to  such  an  extent  as  to  produce  dystrophia  adijwso- 
genitalis.     There  are  many  cases  of  this  character  on  record. 

On  the  other  hand,  it  is,  of  course,  obvious  that  extreme 
hyperplasia  and  other  causes  of  enlargement  of  the  anterior 
lobe  will  produce  pressure  on  the  posterior.  Yet  all  the  evidence 
in  our  possession  seems  to  point  to  the  fact  that  insufficiency 
of  the  pars  posterior  is  not  primarily  the  cause  of  dystrophia 
adiposogenitalis,  especially  as  the  whole  of  this  part  of  the 
pituitary  can  be  removed  without  causing  symptoms.  It  seems 
to  me  more  probable  that  in  these  circumstances  the  syndrome 
may  be  caused  by  the  pressure  produced  by  enlargement  of  the 
pars  anterior  on  the  cells  themselves,  and  on  the  blood-sinuses. 

1  Fischer,  B.,  Hypophysis,  Akromecjalie  und  Fettsucht,  Wiesbaden,  1910. 

2  Erdheim,  J.,  Sitz.  d.  k.  Akad.  d.   Wissensch.  Math-naturw.  Kl,  Wien,  190-1, 
cxiii,  537. 

3  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


HYPOPITUITARISM  247 

The  typical  histological  appearance  of  the  pars  anterior  from 
a  case  of  dystrophia  adiposogenitalis  is  shown  in  figure  161.  The 
cells  are  shrunken  and  widely  separated,  just  as  they  are  in  the 
pituitary  of  the  dog  in  which  this  syndrome  has  been  produced 
by  separation  or  compression  of  the  infundibular  stalk  (fig.  Ill, 
p.  164). 


*  -**•.-••  ill  /•      *•*- 


♦  '. 


Fig.   161. 

Section  of  the  pars  anterior  from  a  case  of  dystrophia  adiposogenitalis  in  a  young 
man,  showing  intense  atrophy  of  the  cells.  (From  a  section  kindly  lent  by 
E.  E.  Glynn.) 

X  150. 

It  appears,  then,  that  the  state  of  adiposity  with  genital 
atrophy  is  due  to  interference  with  secretory  function  or  the 
blood-supply  of  the  pituitary  as  a  whole,  and  that  some  of  the 
symptoms  can  be  mitigated,  as  we  have  seen,  by  injections  of 
infundibulin  and  some  by  the  extract  of  the  anterior  lobe. 
Thus  again  we  have  evidence  that  the  pituitary  is  one  organ 
and  not  two. 


PLURIGLANDULAR   AFFECTIONS    IN    PRIMARY 
LESIONS    OF    THE    PITUITARY 

Of  the  physiological  relationships  between  the  pituitary  and 
the  other  hormonopoietic  organs  we  have  had  some  proof  in 
the  extirpation  experiments  already  recounted  ;  and  of  the 
alterations  which  may  occur  in  distant  organs  of  internal  secretion 
with  pathological  lesions  of  the  pituitary  we  have  had  an  indica- 
tion in  respect  of  the  gonads,  in  which  retrograde  changes  may 
form  a  characteristic  symptom  of  the  diseases  in  question.  It 
will  be  well,  however,  shortly  to  consider  the  question  in  more 
detail,  for  undoubtedly  some  of  the  symptoms  of  hyperpituit- 
arism and  hypopituitarism  are  dependent  not  on  the  lesions 
in  the  pituitary  but  rather  on  those  in  other  hormonopoietic 
organs. 

Gonads. — We  have  seen  that  the  metabolism  of  hyper- 
pituitarism is  largely  concerned  in  the  retention  of  the  lime  and 
magnesium  salts.  This  is  a  masculine  characteristic  ;  con- 
sequently it  is  not  surprising  to  find  other  evidence  of  emphasized 
male  characterization  in  this  state.  /Attention  has  been  called 
to  the  fact1, 2  that  in  the  early  stages  of  acromegaly  in 
men  there  is  often  increased  sexuality.  No  doubt  this  is 
directly  dependent  on  the  hypophysial  lesion.  In  women,  on 
the  other  hand,  hyperhypophysism  causes  the  immediate  cessa- 
tion of  menstruation,  and  in  a  short  time  the  assumption  of 
male  secondary  characteristics. 

There  can  be  little  doubt,  then,  that  there  is  a  close  con- 
nexion between  the  gonads  and  the  pituitary  ;  and  the  difference 
in  the  two  sexes  is  interesting,  and  may  in  part  be  related  to  the 
effect  pituitary  lesions  are  believed  to  have  on  the  suprarenals. 

1  Gushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Buday,  K.,  and  N.  Iansci,  Deutsch.  Arch.f.  Klin.  Med.,  1898,  lx,  385. 


PLURIGLANDULAR   COMPLICATIONS  249 

Tandler  and  Grosz1,  as  we  have  seen,  came  to  the  conclusion 
that  hyperhypophysism  follows  hypoplasia  in  the  gonads — no 
doubt  from  the  fact  that  ablation  of  the  ovaries  leads  to  eosino- 
philia  and  hyperplasia  of  the  pars  anterior.  I  have  already 
discussed  this  question  and  have  pointed  out  the  unlikelihood 
of  this  suggestion  representing  the  true  state  of  the  case. 

Cushing2  discusses  the  relative  importance  of  the  interstitial 
cells  of  the  gonads  and  the  reproductive  cells,  and  appears  to 
attach  undue  importance  to  the  interstitial  cells  in  the  production 
of  the  secondary  sex-characteristics.  I  have  adduced  evidence 
elsewhere3  which  proves  conclusively  that  these  cells  have  very 
little  influence,  if  any,  in  this  respect.  However,  in  regard  to 
the  subject  under  discussion,  the  matter  is  only  of  importance 
in  connexion  with  the  integrity  of  the  uterus  which  is  dependent 
on  the  interstitial  cells,  and  bears  no  relation  to  sex-character- 
ization, which  may  be  directly  influenced  by  the  pituitary  as 
well  as  by  other  members  of  the  hormonopoietic  system. 

In  the  later  phases  of  acromegaly,  when  there  may  be  hypo- 
pituitarism, there  is  in  both  sexes  genital  hypoplasia  and  a 
tendency  towards  a  neutral  type  in  regard  to  the  secondary  sex- 
characteristics. 

Suprarenals. — It  is  well  known  that  the  suprarenal  cortex 
has  an  important  influence  on  sex-characterization3,  4»  5,  and 
the  medulla  a  pressor  action  on  the  blood-pressure. 

In  many  cases  of  pituitary  disease  there  seems  to  be  asso- 
ciated asthenia,  with  a  low  blood-pressure  and  pigmentation. 
In  these  circumstances  the  suprarenals  have  been  found  to  be 
very  small.  A  typical  case  of  this  character  is  shown  in  figure 
1G2.  The  patient  was  deeply  pigmented — even  having  patches 
on  the  sclcrotics — and  the  other  symptoms  of  Addison's  disease 
were  pronounced  ;  at  the  same  time  there  was  well-marked 
acromegaly.  Cushing2  records  eases  in  which  '  hypcrsupra- 
renalism '  existed  in  association   with  hypopituitarism. 

In    a    case,    from    which    I    have    had    the    opportunity    of 

1  Tandler,  J.,  and  8.  Gro^z,  Wien.  Klin.  Woch.,  1907,  xx,  1596. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

3  Bell,  W.  Blair,  The  Sex  Complex,  1916. 

4  Bulloch,  W.,  and  J.  H.  Sequeira,  Trans.  Path.  Soc.,  1905,  lvi,  189. 

5  Glynn,  E.  E.s  Quart.  Jowrn.  Med.,  1:112,  v.  L57. 


250     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

examining  sections,  and  in  which  a  young  woman  developed 
masculine  characteristics  with  amenorrhcea,  there  was  a  chromo- 
phobe adenoma  in  the  pars  anterior  of  the  pituitary  (fig.  163) 
and  a  hyperplastic  tumour  in  the  suprarenal  cortex  (fig.  164). 
Both  these  lesions  would  produce  masculinity  in  a  woman,  and 
increased  masculinity  in  a  man.  In  the  case  recorded  there 
were  no  symptoms  other  than  those   mentioned. 


Fig.  162. 
A  case  of  combined  Addison's  disease  and  acromegaly  in  a  man. 

Thymus. — Experimental  evidence  has  shown  that  de- 
structive lesions  of  the  pituitary  are  associated  with  a  normal 
or  hyperplastic  thymus  ;  but,  on  the  other  hand,  we  must  re- 
member that  after  oophorectomy  or  removal  of  the  testes  there 
is  eosinophil  hyperplasia  in  the  pars  anterior  together  with 
enlargement  of  the  thymus.  This  apparently  paradoxical  state 
of  affairs  indicates  that  probably  the  thymus  is  unaffected  by 
affections  of  the  pituitary,  and  that  if  it  be  enlarged  in  these 
circumstances  this  is  due  to  the  genital  hypoplasia  which  co- 
exists with  most  pituitary  lesions. 

Thyroid. — The    results    of   experimental    thyroidectomy    and 
partial  removal  of  the    pituitary  lead  us    to  conclude    that  the 


PLURIGLANDULAR   COMPLICATIONS  251 

thyroid  and  pars  anterior  are  closely  related,  and  that  as  an 
immediate  result  of  the  extirpation  of  one  of  these  organs 
there  is  a  change  in  the  other  ;  this,  however,  is  much  more 
decided  in  the  pituitary  than  in  the  thyroid. 

It  has  already  been  mentioned  (p.  232)  that  Furnivall  has 
found  the  thyroid  affected  in  a  large  number  of  primary 
pituitary  lesions. 


-.,  .,  °j$?  -  v  -,S?    "*<*<*    ;« 


>-.':.  •  -  ..  ..:.  •  -V-.:-:-    •;.••:-.::••.  ■'.•-.'*   ^  **  *&\<*,^%T* 

•  .;.•:■■■■:■:•       ■:      •       •.     ■..  •.-    ....    ;    ...  ■•,.;■      / 

v.-.v>;  -::-- ;'V.'- *  *..•:.•  ;'•*.•. :*.  •  ■■:;■■:.•. i.'^^-v 


""'  ;■-  ^-'  . 


Fig.  163. 

Section  of  the  pars  anterior  of  the  pituitary  of  a  young  woman  who  had 
developed  masculine  characteristics,  showing  a  chromophobe  tumour  in  the  lower 
part.     (From  a  section  kindly  lent  by  J.  Anderson.) 

X  60. 

Pineal.— We  have  no  definite  information  of  any  con- 
nexion between  pituitary  lesions  and  affections  of  the  pineal. 
It  is,  however,  believed  from  experimental  and  pathological 
evidence  that  the  pineal  is  related  to  the  development  of  sex- 
characteristics,  and  that  a  decreased  function  in  this  organ 
before  puberty  leads  to  sexual  precocity  in  boys.  It  is  doubtful 
whether  the  pineal  has  any  genital  functions  after  puberty, 
or  is  related  to  the  alterations  in  the  sexual  functions  and 
characteristics  associated  with  pituitary  lesions. 


252     DISORDERS   ASSOCIATED   WITH  THE  PITUITARY 


Si  •'. :  P.'\  -■::'::--^\:-:X:/.;:':'.:^--.'.::  K; ..-:-' "•■■>■'■'•  ".■•■' 


» 


^/l|  '"■■  ':'^:-:S.:^^Vv::v^; 


A'.v:- 


"v    •  •    •  ■- -  '    '■■'.•.•.••■•.."-'.'•  •:'  .  V-.  '  .  '■ .   -"  •  •  ■■:  ■    ■'' ^-    '  '. 

Fig.  164. 

Section  of  the  suprarenal  of  a  young  woman  who  developed 
masculine  characteristics,  showing  encapsuled  hyperplasia  in  the 
lower  part  of  the  picture.    {From  a  section  kindly  lent  by  J.  Anderson.) 

X  60. 


PRIMARY  LESIONS  IN  THE  PITUITARY  PRO- 
DUCING SYMPTOMS  NEITHER  OF  EXCESSIVE 
NOR    OF    DIMINISHED    SECRETION 

It  not  infrequently  happens  that  extensive  lesions  occur  in  the 
pituitary  body  which  are  associated  with  but  few  symptoms. 
In  these  circumstances  the  patients  may  complain  only  of  dis- 
turbances of  vision,  but  sometimes  they  suffer  also  with  head- 
aches. As  a  rule,  therefore,  they  consult  an  oculist  in  the  first 
instance. 

In  one  case  of  this  character,  which  came  under  my  notice, 
the  patient,  an  unmarried  lady  42  years  of  age,  was  completely 
blind  in  the  left  eye  and  had  a  very  restricted  field  of  vision  in 
the  right  eye.  At  no  time  had  there  been  either  vomiting  or 
headache.  The  menopause  had  occurred  somewhat  prema- 
turely a  few  years  previously.  The  patient  had  never  exhibited 
symptoms  either  of  acromegaly  or  of  dystrophia  adiposogenit- 
alis.  There  was  a  moderately  raised  carbohydrate -tolerance 
(200  grammes  of  lsevulose),  but  this  is  not  unusual  after  the 
menopause.  There  was  no  thermic  reaction.  The  systolic 
blood-pressure  was  raised  and  was  equal  to  about  140  mm.  of 
mercury.  A  radiograph  showed  that  the  sella  turcica  was  con- 
siderably enlarged  backwards  (fig.  165). 

It  is  probable  that  in  this  ease  portions,  at  least,  of  every 
part  of  the  pituitary  were  functionating,  and  that  there  was 
some  cystic  lesion  present  in  the  anterior  lobe.  The  patient, 
however,  refused  operation. 

There  is  a  large  number  of  these  cases  now  on  record  ;  and 
they  appear  to  be  readily  recognized  by  oculists  as  a  typical 
class  of  case  about  which  not  infrequently  they  are  con- 
sulted1. 

This  seems,    therefore,   the   most   suitable   place   in   which    to 

1  Discussion,  Proc.  Roy.  Soc.  Med.  {Neurol,  and  Ophthalmol.  Sects.),  1913,  vi,  i. 


254     DISORDERS   ASSOCIATED   WITH   THE  PITUITARY 

discuss  the  causation  of  the  ocular  symptoms  with  which 
patients  suffering  from  pituitary  lesions  are  so  often  afflicted. 

The  matter  is  by  no  means  an  easy  one  ;  at  the  same  time 
it  is  one  of  considerable  moment,  since  a  correct  interpretation 
of  the  ocular  anomalies  may  enable  us  definitely  to  decide  in 
which  direction  the  tumour  is  extending,  and  from  which  side  the 
disease  must  be  attacked  when  the  temporal  route  is  employed. 

So  far  as  I  know,  this  point  has  rarely  been  adequately  con- 
sidered in  all  its  bearings,  the  general  assumption  being  that  the 


Fig.  165. 

Radiograph  of  the  skull  of  a  woman  complaining  of  loss  of  sight,  showing 
considerable  enlargement  of  the  sella  turcica.     {By  Thursian  Holland.) 

ocular  symptoms,  scotoma  and  hemianopia,  are  due  to  primary 
optic  atrophy  from  the  direct  pressure  on  the  chiasma  pro- 
duced by  the  enlarging  pituitary.  Such  an  explanation,  how- 
ever, is  not  entirely  satisfactory,  for  a  patient  may  become 
totally  blind  in  one  eye  without  the  other  being  appreciably 
affected. 

A  short  consideration  of  the  anatomy  of  the  optic  tracts 
and  of  the  oculomotor  nerves  is  necessary  to  make  clear  the 
difficulties  that  may  arise  in  connexion  with  this  question. 

It  is  generally  accepted  that  the  fibres  connected  with  the 


LESIONS   OF   THE   OPTIC   TRACT  255 

retinae,  on  which  sight  depends,  have  a  peculiar  course  ;  that  is 
to  say,  those  on  the  nasal  sides  of  the  retinae  decussate  in  the 
optic  chiasma,  as  illustrated  in  figure  166,  while  those  on  the 
temporal  sides  have  a  more  direct  course,  and  are  enclosed  below 
and  at  the  sides  by  the  decussating  fibres  from  the  opposite  eye. 
The  nasal  fibres  of  the  maculopapillary  bundle,  which  is  con- 
cerned with  acute  vision  at  the  macula,  decussate,  while  those 
from  the  temporal  side  of  the  macula  do  not  do  so. 

Now,  the  pressure  of  the  enlarging  pituitary  body  is  exerted 
chiefly  backwards,  and  only  slightly  forwards.  This  is  shown  in 
most  radiographs  by  the  erosion  and  destruction  of  the  posterior 
clinoid  processes  and  the  posterior  wall  of  the  sella  turcica 
(figs.  141,  143,  144,  160  and  165),  due,  no  doubt,  to  the  lesser 
resistance  behind ;  consequently  in  these  circumstances  the 
pressure  must  be  exerted  away  from  the  optic  chiasma,  and 
not  entirely  on  it.  But  the  enlargement  and  resulting  pressure 
is  not  only  backwards,  but  laterally  as  well. 

If,  however,  the  chiasma  be  involved  the  pressure  of  the 
growing  tumour  will  affect  the  fibres  from  the  nasal  fields 
of  the  retinae,  and  the  anterior  and  posterior  commissures  of 
Stilling  and  Gudden  respectively,  which,  however,  are  believed 
to  be  unconnected  with  vision.  Pressure  on  the  optic  chiasma 
forwards  will,  then,  usually  produce  the  well-known  ocular 
symptom  of  bitemporal  hemianopia,  since  the  rays  of  light  from 
the  temporal  fields  impinge,  after  passing  through  the  lenses, 
on  the  nasal  sides  of  the  retinae  (fig.  166)  ;  and  also  in  some  cases 
central  scotoma  or  scotomata  may  be  caused  by  injury  to  the 
nasal  fibres  of  the  highly  differentiated  and  easily  damaged 
maculopapillary  bundles,  which  pass  through  the  chiasma. 
It  is  doubtful  if  the  direct  (temporal)  fibres  can  be  much 
affected  by  pressure  in  this  region.  On  the  other  hand,  as 
already  indicated,  it  is  certainly  more  usual  for  the  optic  tracts 
to  be  involved  by  extension  backwards  and  laterally  of  the 
pituitary  enlargement. 

Fisher1  has  shown  that  the  field  of  vision  is  not  only  first 
limited  on  the  temporal  side,  but  also  from  above  downwards  ; 
further,  this  writer2  agrees   with  dishing3  that  the  colour-vision 

1  Fisher,  J.  H.,  Tran*.  OpMh.  Sue  Unit.  Kingdom,  1911,  xxxi,  51. 

2  Fisher,  J.  H.,  Proc.  Roy.  Soc.  Med.  (Netirol.  and  Oj)hthalmol.  Sects.),  1913, 
vi,liii. 

3  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


256 


R.   OPTIC   NERVE 

PITUITARY    BOD? 

R.   PEDUNCLE 
R.   OPTIC  TRACT 


SIXTH   NERVE 

INTERNAL  GENICULATE   BODY 

SUPERIOR  COLLICULUS 


OPTIC    RADIATIONS 


THIRD  NERVE 

FOURTH  NERVE 

SUDDEN'S  COMMISSURE 

PULVINAR 

EXTERNAL  GENICULATE  BODY 


NUCLEUS  OF  THIRD   NERVE 


-NUCLEUS  OF  FOURTH   NERVE 


NUCLEUS  OF  SIXTH    NERVE 


R.   OCCIPITAL    AREA X—  ,_ 


Fig    166. 


Diagram  illustrating  the  optic  nerves  and  tracts  and  the  fields  of  vision.     The 
possible  directions  of   extension  of   enlargements  of  the  pituitary  are  shown  by 


LESIONS    OF    THE    OPTIC   TRACT  257 

disappears   before  the  form-vision.      Fisher1    states   that    in    his 

opinion  the    ocular    symptoms    can    be    only    explained    on   the 

assumption  that  there  is  a  dragging  or  stretching  of  the  fibres  in 

the    optic   tract    of   the    side  opposite  to    that  on    which    direct 

pressure  is  being  exerted.     He  says  :  "  My  cogitations  are  leading 

me  to  the  conclusion  that  the  visual  phenomena  in  many  of  the 

cases  are  explained  by  traction  effects  on  the  visual  pathways  as 

the  tumour  extends  upwards  behind  the  chiasma  and  between 

the  optic  tracts  in  the  interpeduncular  space.     A  tumour  fairly 

symmetrical   in   outline   would   stretch  the   decussating  fibres   in 

the  chiasma,  while  in  no  way  dragging  on  the  direct  fibres,  and 

give   us   a   bitemporal    hemianopia  ;     it    is    conceivable   that   the 

highly  specialized  function  of  the  macular  fibres  might  be  more 

readily   injured   than  that   of  the   other   fibres   in  the   chiasma  ; 

on  a  traction  hypothesis  the  expanding    scotoma  cases  are  to  be 

understood,     and    hemiachromatopia    can    be    recognized    as    a 

symptom  which  it  would  be  very  difficult  to  accept  on  a  direct 

pressure    hypothesis.      If     the     tumour     mass,    having    already 

caused    a    bitemporal    hemianopia,    increased    now    more   to    the 

right  than  to  the  left  side,   it  would  probably  drag  on  the  left 

optic  nerve  as  a  whole,  or  accentuate  the  angle  between  the  left 

optic  nerve  and  the  left  optic  tract  ;    in  either  way  the  fibres 

from  the  temporal  half  of  the  left  retina  would  now  suffer  by 

dragging,    and  the  eye  would  be  rendered    blind  ;    the    tumour 

expanding   to   the    right    would    diminish  the    acuteness    of   the 

angle  or  curve  formed  by  the  right  optic  nerve  and  the  right 

tract,  and  the  uncrossing  fibres  from  the  right  retina  might  long 

preserve    their    function.      A    pituitary   tumour    growing    in  the 

interpeduncular    space   asymmetrically  and   from   the  first  lying 

more  to  the  right  than  to  the  left  of  the  median  line  might,  I 

think,   be  expected  to  injure   by   traction   first   the   decussating 

fibres  from   the   left   optic   nerve    and  then   its    non-decussating 

fibres  before  any  fibres   of  the  right  optic  nerve  became  unduly 

stretched  ;    as  the  crossing  fibres  from  the  right  retina  became 

involved,  loss  of  temporal  field  on  this  side   would  be  expected 

to  occur,  either  centrifugally  or  centripetally.    The  possibility  that 

a  displaced  optic  nerve  may  receive  injurious  pressure  from  the 

bony  optic  foramen  on  that  side  towards  which  it   is  displaced 

1  Fisher,  J.  H.,  Proc.  Roy.  Soc.  Med.  {Neurol,  ami  Ophthalmol.  Sects.).   1913, 
vi,  liii. 

17 


258     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

can  also  be  conceived.  In  the  rarer  cases  of  homonymous 
hemianopia  direct  pressure  on  the  optic  tract  concerned  is,  no 
doubt,  the  true  explanation  ;  in  the  tract  the  uncrossed  fibres 
seem  to  be  afforded  the  more  sheltered  situation." 

Further,  I  do  not  think  it  has  been  sufficiently  emphasized 
how  frequently  there  is  some  degree — often  very  considerable 
— of  oculomotor  paresis  on  one  side.  The  close  relationship 
of  the  third  nerve  to  the  pituitary  (fig.  166)  accounts  for  the 
great  frequency  with  which  it  is  involved  in  the  pressure  pro- 
duced by  an  enlarging  pituitary  tumour.  I  think,  too,  that  in 
the  paresis  of  this  nerve,  which  produces  the  symptoms  of  ex- 
ternal squint  with  diplopia  and  possibly  nystagmus,  we  have 
the  most  important  evidence  as  to  the  direction  in  which  the 
tumour  is  extending ;  that  is  to  say,  the  lateral  pressure  is 
greatest  on  the  side  on  which  there  is  evidence  of  paresis  of  the 
third  nerve. 

Sometimes  the  fourth  and  sixth  nerves  are  affected. 

It  is  necessary,  also,  to  bear  in  mind  the  possibility  of  in- 
direct pressure  from  a  large  tumour,  either  of  the  pituitary  or 
in  the  neighbourhood,  on  the  lower  visual  centres  (fig.  166). 
Such  a  phenomenon  might  lead  to  very  confusing  ocular 
symptoms. 


§  ii.   SECONDARY   LESIONS    OF    THE    PITUITARY 


NEIGHBOURING    PATHOLOGICAL    CONDITIONS 

Hydrocephalus. — -Although  Marienesco  and  Goldstein1  in 
1909,  and  later  Goldstein2  described  cases  of  dystrophia  adiposo- 
genitalis  associated  with  hydrocephalus  and  supposed  mening- 
itis, to  Gushing3  belongs  the  credit  of  definitely  calling  attention 
to  the  connexion  between  hydrocephalus  and  pituitary  lesions. 
The  last-named  surgeon  quotes  several  illustrative  cases.  In 
one  of  these  there  was  a  cerebellar  cyst  giving  rise  to  moderate 
ventricular  hydrocephalus,  and  the  symptoms  pointed  to  hyper- 
hypophysism — that  is,  acromegaly.  In  other  cases  of  hydro- 
cephalus from  various  causes — congenital  and  new  growths — 
there  was  hypopituitarism. 

We  have  seen  (p.  245)  that  dishing  believes  that  hydro- 
cephalus produces  pressure  on  the  posterior  lobe,  particularly 
through  the  infundibulum.  But,  as  I  have  already  stated,  the 
infundibulum  in  man  is  not  hollow  ;  consequently  the  pressure 
should  be  evenly  distributed  on  the  pituitary  as  a  whole,  or 
on  the  blood-supply  ;  and  this  is  borne  out  by  Cushing's  own 
cases.  In  the  first  (case  xxxviii)  there  was  hyperhypophysism, 
due  no  doubt  to  irritation  of  the  anterior  lobe,  for  the  ventricular 
pressure  was  only  moderate.  In  the  other  cases  the  pressure 
was  greater  and  the  anterior  lobe — according  to  the  illustrations 
given — suffered  equally  with  the  posterior  lobe  ;  indeed,  the 
whole  appearance  is  that  of  a  pituitary  in  which  there  had  been 
interference  with  the  blood-supply. 

Neurath4,  also,  has  reported  cases  apparently  of   hyperplasia 

1  Marienesco,  G.,  and  K.  Goldstein,  Nouv.  Icon,  tie  la  Xalpetritre,  1909,  xxii,  628. 

2  Goldstein,  K.,  Arch.  f.  Psychiat.,  1910,  xlvii,  126. 

3  Gushing,  H.,  The  Pituitary  Body  and  its  disorders,  1912. 

4  Neurath,  R.,  Wien.  Klin.  Woch.,  1911,  xxiv,  43. 


260     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

in  the  anterior  lobe  with  skeletal  overgrowth  in  association  with 
hydrocephalus. 

Cushing  raises  another  point  which  is  open  to  criticism.  He 
states  that  in  these  circumstances  there  is  stasis  in  regard  to  the 
secretion  of  infundibulin  ;  that  the  intraventricular  tension  is 
such  that  the  secretion  cannot  be  poured  into  the  cerebrospinal 
fluid  in  normal  quantities.  As  the  whole  question  of  the  destina- 
tion and  method  of  conveyance  of  infundibulin  to  the  body-fluids, 
and  indeed,  of  the  vital  importance  of  this  hormone  is  by  no 
means  settled,  we  are  not  in  a  position  to  discuss  this  matter 
further.  Attention  may  be  called,  however,  to  what  has  been 
said  from  a  physiological  point  of  view  on  page  102  and  following. 


Fig.  167. 

A  cholesteatoma  in  the  neighbourhood  of  the  pituitary  which  exerted  pressure 
on  that  organ  and  so  caused  dystrophia  adiposogenitalis.  (Fro?n  a  specimen  kindly 
lent  by  E.  E.  Glynn.) 

+  h 

Neighbouring  tumours.— A  growth  such  as  a  glioma  or 
an  endothelioma,  or  possibly  a  gumma,  in  the  neighbourhood  of 


NEIGHBOURING    PATHOLOGICAL   CONDITIONS       26J 

the  pituitary  may  give  rise  to  some  of  the  symptoms  of  pituitary 
tumours,  especially  headaches  and  ocular  disturbances.  With 
these  we  are  not  at  the  moment  concerned.  But  neighbouring 
tumours  may  produce  pressure  on  the  pituitary  and  lesions 
therein.  If  the  pressure  be  moderate  there  may  be  glycosuria 
and  other  symptoms  of  hyperpituitarism ;   when  the  pressure  is 


Fig.  168. 

Erosion  of  the  right  posterior  clinoid  process  caused  by  the  tumour  shown  in 
figure  167.     {From  a  specimen  kindly  lent  by  E.  E.  Glynn.) 

XI. 

considerable  hypopituitarism  will  be  caused.  If  the  growth  be 
more  or  less  centrally  placed  (fig.  167)  diagnosis  may  be  somewhat 
difficult,  although  a  radiograph  should  show  little  or  no  enlarge- 
ment of  the  sella  turcica,  and  this  would  help  us  to  exclude  a 
primary  pituitary  lesion.  Nevertheless,  even  in  these  circum- 
stances the  posterior  clinoid  processes  may  be  eroded  (fig.  168) 
— a  lesion  which  may  lead  to  the  supposition  that  the  pituitary 
fossa  is  enlarged  in  a  backward  direction,  as  is  usually  the  case 
with  a  primary  pituitary  tumour. 


DISEASES  OF    THE    OTHER    HORMONOPOIETIC    ORGANS 

Lesions  of  the  thyroid. — From  the  close  relationship  between 
the  pituitary  and  thyroid,  to  which  attention  has  been  directed, 
we  would  expect  to  find  that  the  pituitary  is  affected  in  diseases 
of  the  thyroid,  which  arc  very  common  in  women  ;  and  such  is 
the  case. 

I  have  had  the  opportunity  of  examining  the  organs  from  a 
case  of  a  cretinism,  and  as  the  appearances  of  the  pituitary  are 
somewhat  remarkable  it  may  be  worth  while  to  describe  them  in 
some  detail. 

In  this  case — a  female  subject,  33  years  of  age — the  pituitary 
was  found  on  macroscopical  examination  to  be  about  the 
maximum  average  size  in  an  adult,  measuring  1*5  cm.  in  the 
antero  -posterior  diameter  and  0-7  cm.  in  the  superior-inferior 
diameter.  Unfortunately  the  transverse  diameter  was  not  recorded, 
but   it  appeared  to  correspond  with  the  other  measurements. 

On  histological  examination  the  first  point  noted  was  that  the 
organ  is  enclosed  in  a  dense  fibrous  tissue  capsule,  from  which 
it  cannot  readily  be  separated.  The  pars  anterior  is  for  the 
most  part  composed  of  chromophobe  cells  ;  there  are  extremely 
few  eosinophil  cells,  and  only  occasional  collections  of  lightly 
staining  basophil  cells  around  the  periphery.  Large  masses  of 
secretion,  which  appear  to  be  formed  by  a  syncytial  confluence 
of  chromophobe  cells,  are  scattered  throughout  the  pars  anterior 
(fig.  169).  A  considerable  number  of  colloid-acini  are  to  be 
seen  in  the  pars  intermedia,  and  there  is  much  neutrophil 
granular  secretion  underlying  the  pars  intermedia  and  extend- 
ing in  a  branching  fashion  into  the  pars  nervosa  (fig.  170),  the 
neuroglia-fibres  of  which  have  a  '  teased-out  '  appearance. 

These  characteristics  of  the  intrinsic  structure  of  the  pituitary 
indicate  considerable  activity,  which  is  probably  compensatory  in 
character. 


DISEASES   OF   OTHER  HORMONOPOIETIC    ORGANS    263 
*      «••  e  <»  •  •»   *v    »e 

•         '     .<•>; '*•"•**•*»    * 

o  I  „°  '  -.  •  ft 

*  .'(.»'«»  4  •  I  I 

•  •/  '  »  .    j '  *<?     *     ^ « 

'■§  .  °  «       •     o 

I  *      9  a 

.  • .  #••  V  °  •     * "     •    £ 

Fig.  169. 

Section  of  the  pars  anterior  of  a  cretin,  showing  masses  of  secretion  among 
chromophobe  cells  and  a  few  basophils. 

X  200. 


8           « 

• 

* 

*                  *  s 

«* 


Fig.  170. 

Section  of  the  pituitary  of  a  cretin,  showing  secretion  extending  from  the 
pars  intermedia  into  the  pars  nervosa. 

X  100. 


264     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

In  myxcedema  associated  changes  in  the  pituitary  were  first 
described  by  Boyce  and  Beadles1  and  by  Comte2.  They  observed 
general  enlargement  of  the  organ  and  found  histologically  an 
increase  in  the  chromophobe  cells  in  the  pars  anterior,  and  they 
noted,  also,  the  masses  of  secretion  that  I  have  already  mentioned 
as  occurring  in  the  cretin.  Fry3,  too,  has  recently  described 
the  pituitaries  from  two  cases  of  myxcedema.  He  found  changes 
somewhat  similar  to  those  which  I  have  already  specified. 
There  was,  however,  in  his  cases  eosinophil  as  well  as  basophil 
colloid  in  the  pars  anterior,  and  a  large  number  of  basophil 
cells. 

It  appears  probable  from  the  scanty  evidence  before  us  that 
there  is  a  very  considerable  increase  in  the  activity  of  the 
pituitary  as  shown  by  the  histological  appearances  of  the  pars 
anterior  in  cretinism,  and  a  rather  less  pronounced,  but  similar, 
change  in  myxcedema,  in  which  disease  there  are  different  degrees 
of  insufficiency,  but  never  entire  suppression  of  the  thyroid 
function  as  in  cretinism. 

In  parenchymatous  goitre,  in  which  condition  there  is  pre- 
sumably a  low  degree  of  thyroid  activity,  I  have  found  in  the 
pars  anterior  universal  chromophobia  with  a  well-marked  acinous 
arrangement  in  the  cells  enclosing  secretion  (fig.  171),  and  neutro- 
phil colloid  in  the  pars  intermedia  (fig.  172).  The  pars  nervosa 
appears  to  remain  normal  in  these  circumstances. 

Fry3  has  described  the  pituitary  from  a  patient  with  goitre, 
the  histological  appearances  of  which  were  those  of  a  cystic 
adenoma.  In  this  case  there  was  a  large  number  of  eosinophil 
cells  in  the  pars  anterior,  and  in  the  pars  posterior  there  was  a 
considerable  amount  of  colloid.  These  phenomena  indicate  a 
moderate  degree  of  thyroid  insufficiency  with  the  required  com- 
pensatory effort  on  the  part  of  the  pituitary. 

In  exophthalmic  goitre  I  have  found  in  the  pars  anterior  many 
more  basophils  than  normal  ;  indeed,  most  of  the  cells  appear 
to  be  basophil  (fig.  173),  with,  perhaps,  a  few  in  a  transitional 
stage  between  eosinophilia  and  basophilia.  The  pars  posterior 
is  normal.  This  appearance  indicates,  of  course,  a  condition 
of  inactivity  ;    and  is  in  keeping  with  what  has  already  been  said 

1  Boyce,  R.,  and  C.  F.  Beadles,  Journ.  Pathol,  and  Bacteriol.,  1893,  i,  223. 

2  Comte,  L.,  Zeiglers  Beitr.  z.  Pathol.  AnaL,  1898,  xxiii,  90. 

3  Fry,  H.  J.  B.,  Quart.  Journ.  Med.,  1915,  viii,  277 


DISEASES   OF   OTHER  HORMOXOPOIETIC   ORGANS    265 


?* 


W 


Fig.   171. 


Section  of  the  pars  anterior  in  a  case  of  parenchymatous  goitre,  showing 
an  acinous  arrangement  of  chromophobe  cells.     (Photomicrograph.) 

X  150. 


m 


«al& 


Fig.  172. 


Section  of  the  pituitary  in  a  case  of  parenchymatous  goitre,  showing  neutrophil 
colloid  in  the  pars  intermedia.     (Photomicrograph.) 

X  100. 


266     DISORDERS   ASSOCIATED    WITH   THE   PITUITARY 

in    regard    to    the   relationship    between    the   thyroid    and   pars 
anterior  of  the  pituitary. 

Lesions  of  the  gonads. — We  have  already  seen  that  Tandler 
and  Grosz1  and  others  assert  that  acromegaly  is  the  result  of 
insufficiency  in  the  secretory  functions  of  the  gonads,  but  I  regard 
this  view  as  untenable.  It  cannot,  however,  be  denied  that 
changes  occur  in  the  pars  anterior  as  the  result  of  ovarian  and 
testicular    insufficiency — we    have    ample    experimental    evidence 


Fig.  173. 

Section  of  the  pars  anterior  in  a  case  of  exophthalmic  goitre,  showing  col- 
lections only  of  basophil  cells  separated  by  large  blood-sinuses,  and  shrunken  owing 
to  imperfect  fixation. 

X  200. 

pointing  in  this  direction  ;  and  the  evidence  indicates  that  with 
insufficiency  in  the  gonads  there  is  increased  eosinophilia  in  the 
pars  anterior. 

It  is  possible  that  the  skeletal  overgrowth  which  may  occur 
when  puberty  is  delayed  owing  to  retardation  in  the  develop- 
ment of  the  gonads  is  occasioned  by  hyperplasia  in  the  pituitary, 
but   of   this    we    have   but   little    definite   pathological    evidence. 

1  Tandler,  J.,  and  S.  Grosz,  Wien.  Klin.  Woch.,  1907,  xx,  1596;  idem,  1908, 
xxi,  277. 


DISEASES    OF   OTHER  HORMOXOPOIETIC    ORGANS    267 

It  is  probable,  however,  that  the  gonads  and  pituitary  are 
antagonistic  to  some  extent,  although  the  integrity  of  either  is 
dependent  on  the  normal  functional  activity  of  the  other.  It 
is  certain,  also,  that  correlated  changes  only  occur  in  the  pituitary 
when  the  functions  of  the  gonads  are  in  excess  of  or  below  the 
normal  :  we  have  no  direct  evidence  concerning  the  changes 
that  may  occur  in  the  pituitary  in  the  first  case  :  but  in  the 
second  there  is  an  obvious  increase  in  the  secretion  of  the  pars 
anterior,  as  is  shown  by  the  eosinophilia  found  in  these  circum- 
stances. 

Lesions  of  the  thymus. — The  only  abnormal  condition  of 
the  thymus  of  which  we  have  any  specific  knowledge  is  that  in 
which  the  thymus  fails  to  undergo  the  normal  involution  that 
is  believed  to  commence  early  in  life  and  to  reach  the  maximum 
about  puberty.  In  some  cases  the  thymus  not  only  fails 
to  undergo  this  involution,  but  even  undergoes  hypertrophy 
with  hyperplasia,  producing  the  well-known  condition  of  status 
lymphaticus.  This  exists  to  some  extent  in  eunuchs  and  in  all 
castrated  animals. 

I  do  not  think  that  many  observations  have  been  made 
in  regard  to  possible  changes  in  the  pituitary  in  these  circum- 
stances. In  one  case  that  I  have  investigated  there  was  also 
a  parenchymatous  goitre,  to  which  the  alterations  found  in  the 
pituitary  were  probably  due.  In  another  case  of  status  lymph- 
aticus in  a  young  woman  who  died  suddenly  the  genital  organs 
and  functions  were  normal,  and  no  changes  were  detected  in  the 
pituitary.  Fry1  records  a  case  in  which  he,  too,  failed  to  observe 
any  abnormality  ;  and  dishing2,  also,  records  two  cases  in  which 
there  were  pituitary  tumours,  but  in  which  it  was  difficult  to 
trace  any  relationship  between  these  lesions  and  the  hyperplasia 
in  the  thymus. 

It  appears  likely  on  the  evidence  before  us.  especially  of  the 
associated  genital  hypoplasia  which  may  be  present,  that  if  any 
changes  were  to  be  found  in  the  pituitary  as  the  result  of  the 
status  lymphaticus  they  would  be  of  the  nature  primarily  of  an 
increased  function  with  appropriate  changes  in  the  cells  of  the 
pars  anterior. 

1  Fry,  H.  J.  B.,  Quart.  Joum.  Med.,  1915,  viii,  277. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


268     DISORDERS   ASSOCIATED    WITH   THE   PITUITARY 

Lesions  of  the  suprarenals. — We  have  already  seen  that  acro- 
megaly may  be  associated  with  lesions  of  the  suprarenals,  but  no 
satisfactory  pathological  evidence  of  changes  in  the  pituitary  as 
the  direct  result  of  Addison's  disease  or  hyperplasia  of  the  supra- 
renals has  been  adduced.  In  the  case  recorded  by  Anderson1 
there  were  hyperplastic  lesions  both  in  the  suprarenal  cortex  and 
the  pars  anterior  of  the  pituitary  (p.  249). 

Lesions  of  the  pancreas.— Glycosuria  is  so  often  associated 
with  disease  of  the  pituitary  that  only  in  those  cases  in  which 
definite  lesions  in  the  pancreas  have  also  been  found  in  diabetes 
can  we  look  upon  changes  in  the  pituitary  as  possibly  secondary 
to  the  pancreatic  lesion. 

Fry2  has  made  a  number  of  investigations  in  which  the  lesions 
in  the  pancreas  were  carefully  investigated.  He  came  to  the 
conclusion  that  histological  changes  in  the  pituitary  are  un- 
noticeable  with  acute  pancreatitis,  but  that  with  diabetes  (pre- 
sumably of  pancreatic  origin)  there  is  in  the  pars  anterior  an 
increase  in  the  eosinophils,  which  assume  an  adenomatous  arrange- 
ment, and  that  there  is  "  colloid  invasion  of  the  anterior  lobe, 
and  areas  of  cellular  degeneration  ".  The  cellular  degeneration 
mentioned  could  hardly  be  specific,  and  may  have  been  due  to 
imperfect  fixation  of  the  tissues. 

1  Anderson,  J.,  Glas.  Med.  Journ.,  1915,  lxxxiii,  178. 

2  Fry,  H.  J.  B.,  Quart.  Journ.  Med,,  1915,  viii,  277. 


METASTASES 

Sometimes  pituitary  lesions  are  the  result  of  metastatic 
growths  from  distant  sites.  As  a  rule,  the  symptoms  produced 
are  those  of  destructive  or  irritative  lesions  of  the  pituitary. 
As  Fischer1  emphasizes,  there  is  great  individuality  in  regard  to 
various  malignant  tumours  :  sometimes  metastases  produce 
secretion,  at  other  times  they  do  not  ;  some  malignant  tumours 
of  the  pituitary  cause  acromegaly,   and  others  do  not. 

It  is,  however,  hardly  likely  that  a  metastatic  growth  could 
produce  an  excess  of  secretion  of  the  pars  anterior,  as  a  primary 
growth  may  do  ;  for  secondary  growths  invariably  have  the 
structural  characteristics  of  the  parent  growth,  and  if  they 
possess  any  secretory  activity  it  is  of  the  same  quality  as  that 
produced  by  the  original  neoplasm. 

An  interesting  example  of  the  irritative  effect  that  may  be 
caused  by  a  metastatic  growth  in  the  pituitary,  is  that  re- 
corded by  Simmonds2.  The  patient,  a  woman,  from  whom 
a  breast  had  been  removed  two  months  previously  for  cancer, 
developed  obstinate  and  intense  polyuria.  The  quantity  of 
urine  passed  varied  from  10  to  19  litres  a  day.  At  the  necropsy 
the  pars  nervosa  was  found  to  be  entirely  destroyed  by  a  cancer- 
ous metastasis.  This  author  states  that  the  growth  irritated 
the  pars  intermedia,  and  so  caused  diabetes  insipidus  (polyuria) 
with  which  the  patient  suffered. 

Metastases  interfering  with  the  blood-supply  of  the  pituitary 
may  cause  dystrophia  ad'qjosogcnitalis.  should  the  patient 
survive  a  sufficiently  long  period  of  time. 

1  Fischer,  B.,  Hypophysis,  Acromegalic  und  Fettsuchi,  Wiesbaden,  1910. 

2  Simmonds  M„  Munch.  Med.   Woch.,  1913,  lx,  127. 


INFECTIONS 

We  have  seen  in  our  experimental  studies  that  general  and 
even  local  infections  may  affect  the  pituitary  enough  to  produce 
definite  changes  akin  to  hyperplasia  in  the  pars  anterior  ;  and 
we  find  that  these  observations  are  borne  out  by  pathological 
investigations  in  the  human  subject. 

Many  observers1'2,3  have  considered  that  infection  is  an 
etiological  factor  in  the  onset  of  some  cases  of  acromegaly- — that 
is  to  say,  hyperhypophysism  is  often  secondary  to  infectious 
diseases.  Typhoid,  especially,  is  believed  to  be  capable  of  pro- 
ducing a  lasting  effect  owing  to  the  long  duration  of  the  disease. 

It  is  possible,  therefore,  that  functional  hyperplasia  takes 
place  as  a  means  whereby  secretion  in  large  quantities  may  be 
produced  for  the  neutralization  of  toxins  ;  and,  according  to  some, 
this  hyperplasia  may  fail  to  disappear  with  the  termination  of  the 
infection. 

In  general  septicaemia  I  have  found  very  obvious  changes 
in  the  pars  anterior  of  the  pituitary  :  the  cells  are  swollen  and 
cloudy,  and  for  the  most  part  have  a  neutrophil  reaction 
to  stains.  These  chromophobe  cells  are  often  arranged  in 
a  very  definitely  acinous  manner,  such  as  we  see  normally  in 
pregnancy.  The  basophil  cells  may  exist  in  fair  numbers  at  the 
periphery,  but  there  are  very  few  eosinophil  cells. 

In  more  localized  infections,  such  as  that  producing  a  cerebral 
abscess,  exactly  the  same  state  of  affairs  may  be  observed  ;  but  in 
the  cases  examined  the  chromophobe  cells  were  not  found  to  be 
arranged  in  glandular  formation  as  is  the  case  in  severe  generalized 
infections. 

Cushing3  states  that  animals  from  which  parts   of  the  pars 

1  Messedalgia,  L.,  1908  (quoted  by  Cushing3). 

2  Delille,  A.;  Uhypophyse  et  la  medication  hypophysaire,  Paris,  1909. 

3  Cushing,  H..  The  Pituitary  Body  and  its  Disorders,  1912. 


INFECTIONS  271 

anterior  had  been  removed  succumbed  more  easily  to  infections 
than  normal  animals.  This,  however,  must  have  been  a  difficult 
matter  to  prove  satisfactorily. 

There  is  one  phenomenon,  which  is  supposed  to  result  from 
the  hyperplasia  of  the  pars  anterior  due  to  infections,  that  is 
of  peculiar  interest.  I  refer  to  the  growth  that  takes  place  in 
young  persons  in  whom  the  epiphyses  have  not  joined  at  the  time 
they  become  affected  by  some  prolonged  infectious  disorder, 
such  as  typhoid  fever.  This  remarkable  growth,  which  may 
be  represented  by  an  increase  in  stature  of  several  inches 
in  a  few  weeks,  has  been  attributed  to  the  hormone  which 
originates  in  the  pars  anterior  and  stimulates  the  growth  of 
bone.  The  pituitary,  excited  to  excessive  action  by  the  toxin, 
produces  the  hormone  in  larger  quantities  than  normal,  and 
thus,  it  is  supposed,  brings  about  the  result  described. 

It  is  only  right  to  say  that  this  view  has  been  seriously 
questioned,  and  has  no  experimental  support ;  Chanal1,  indeed, 
asserts  that  the  increase  in  growth  which  may  occur,  particularly 
in  typhoid  fever,  is  due  to  the  infective  processes  directly  stimul- 
ating the  epiphyses. 

It  is  important  to  note  that  infections  not  only  lead  to  hyper- 
plasia, but  may  in  some  cases  be  so  intense  as  to  cause  atrophy 
or  necrosis  of  the  pituitary.  Such  a  condition  has  been  described 
by  Simmonds2.  The  patient  died  at  the  age  of  46  years.  Ten 
years  previously  she  had  suffered  with  severe  puerperal  fever, 
following  her  fifth  confinement.  Subsequently,  there  was  com- 
plete amenorrhcea,  and  mental  symptoms  developed,  with  loss 
of  weight  and  general  weakness.  At  the  post-mortem  examina- 
tion the  pituitary  was  found  to  weigh  only  0*3  gramme,  and  on 
histological  examination  very  few  normal  cells  were  to  be  seen 
in  the  pars  anterior. 

Simmonds  states  that  he  has  frequently  found  in  the  pituitary 
bacterial  emboli  and  necrosis  in  these  cases. 

1  Chanal,  J.,  1007  (quoted  by  Cushing,  The  Pituitary  Body  and  its  Disorders 
1012). 

-  Simmonds,  M„,  Deutsch.  Med,  Woch.,  1014,  xl,  322. 


TOXAEMIAS    OF   PREGNANCY 

The  toxaemias  of  pregnancy  are  little  understood  in  regard  to 
the  etiological  factors  ;  consequently  in  recording  coincidental 
changes  in  the  hormonopoietic  organs  we  have  no  clear  knowledge 
as  to  the  cause  of  the  lesions.  Nevertheless,  alterations  in  the 
pituitary  associated  with  toxaemias  of  pregnancy  are  undoubtedly 
secondary  to  the  general  toxaemia  whatever  that  may  be. 

I  know  of  no  observation  or  description  of  the  pituitary  in 
hyperemesis — that  is,  excessive  vomiting  of  pregnancy. 

In  eclampsia  I  have  had  opportunities  of  making  observa- 
tions, and  I  have  found  that  in  this  condition  there  is  an 
abnormal  number  of  basophils  in  the  pars  anterior,  and  a  con- 
siderable eosinophilia  (fig.  174),  whereas  the  so-called  '  preg- 
nancy '  neutrophil  cells  are  not  well  marked.  We  would  expect, 
at  the  late  stage  of  pregnancy  at  which  eclampsia  occurs,  to  find 
normally  a  considerable  number  of  large  neutrophil  cells  and  very 
few  basophils.  The  eosinophilia,  of  course,  is  often  considerable 
in  pregnancy,  and  is  not  abnormal. 

Colloid  is  found  in  the  pars  intermedia  and  in  the  cleft 
(fig.  175),  as  is  usual.  There  may  be,  too,  extensive  invasion 
of  the  pars  nervosa  by  the  cells  of  the  pars  intermedia  (figs.  175 
and  176). 

The  paucity  of  large  neutrophil  cells  in  eclampsia  indicates, 
then,  a  lower  degree  of  activity  than  is  normal ;  while  the 
invasion  of  the  pars  nervosa  may  lead  to  an  excessive  pro- 
duction of  infundibulin. 

In  a  case  of  cortical  necrosis  of  the  kidneys — a  very  rare  com- 
plication of  pregnancy,  and  one  which  is  certainly  due  to  some 
toxaemia — I  found  the  general  quantitative  relationship  between 
the  neutrophil,  basophil  and  eosinophil  cells  to  be  that  normal 
to    the    pregnant    state  ;    but   there    was    a    considerable    degree 


TOXAEMIAS   OF   PREGNANCY 


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Fig.  174. 

Section  of  the  pars  anterior  in  a  case  of  eclampsia,  showing  a  predominance 
of  basophil  cells.     (Photomicrograph.) 

X  100. 


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Fig.  175. 

Section  of  the  pituitary  in  a  case  of  eclampsia,  showing  colloid  in  the 
pars  intermedia  and  cleft,  and  invasion  of  the  pars  nervosa  by  the  cells  of 
the  pars  intermedia.     (Photomicrograph.) 

X30. 
18 


274     DISORDERS    ASSOCIATED    WITH  THE  PITUITARY 


Fig.  176. 

Section  of  the  pars  posterior  in  a  case  of  eclampsia,  showing  masses  of  pars 
intermedia  cells  invading  the  pars  nervosa.     (Photomicrograph.) 

X60. 


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Section  of  the  pars  anterior  in  a  case  of  cortical  necrosis  of  the  kidneys, 
showing  vacuolation  of  the  basophils. 


X  200. 


TOXEMIAS    OF   PREGNANCY  275 

of  vacuolation  of  the  cells,  which  was  most  obvious  in  the  baso- 
phils, owing  to  the  colour-contrast  (fig.  177). 


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Fig.  178. 

Section  of  the  pars  intermedia  in  a  case  of  cortical  necrosis  of  the  kidneys, 
showing  a  large  amount  of  colloid. 

X  40. 

There  seemed  to  be  a  rather  excessive  quantity  of  colloid 
in  the  pars  intermedia  (fig.  178),  although  this  substance  is 
generally  plentiful  in  this  situation  during  pregnancy. 


§  iii.  GENERAL    CONSIDERATION   OF   THE    PATHOLOGY 
OF   THE   PITUITARY 

In  all  that  has  gone  before  it  has  been  very  evident  that 
our  knowledge  of  pathological  lesions  of  the  pituitary  is  still 
imperfect  and  uncertain.  And  it  is  unlikely  that  we  shall  reach 
a  more  scientific  standpoint  until  pathologists  realize  that  no 
post-mortem  examination  is  complete  until  all  the  hormono- 
poietic  organs  have  been  exhaustively  examined.  We  know,  also, 
still  too  little  of  the  age-changes  and  sex-differences  in  the  normal 
pituitary.  Further,  we  have  not  yet  conclusively  and  unanim- 
ously decided  exactly  what  the  situation  and  nature  of  the 
lesion  is  in  many  cases  which  we  associate  with  hyperpituitarism 
and  hypopituitarism  ;  and  we  are  still  confused  by  the  supposed 
morphological  and  physiological  separation  of  the  different  parts 
of  the  pituitary.  Personally,  I  believe  it  to  be  one  organ,  and 
that  it  has  many  functions,  just  as  all  the  other  hormonopoietic 
organs  have  ;  indeed,  I  believe  that  until  we  recognize  the  physio- 
logical unity  of  the  pituitary  body,  we  cannot  reconcile  wrhat  we 
now  look  upon  as  the  conflicting  facts  of  morphology,  physiology 
and  pathology  in  regard  to  this  structure. 

If  the  anterior  and  posterior  lobes  were  separate  and  distinct 
organs,  we  would  expect  to  find  more  evidence  of  their 
independent  importance  in  comparative  anatomy.  We  some- 
times find,  however,  the  reverse  state  of  affairs — striking  examples 
being,  from  one  point  of  view,  the  absence  of  a  pars  nervosa  in 
some  elasmobranchs,  and,  from  the  other,  the  channelling  of  the 
pars  nervosa  by  the  cells  of  the  pars  intermedia  in  the  mono- 
treme  (ornithorhynchus)  (figs.  35  and  36,  p.  57). 

So,  too,  with  respect  to  the  physiology  of  the  pituitary, 
the  whole  sum  of  the  evidence  obtainable — which  I  need  not 
reiterate — points  in  the  same  direction. 

Then,  when  we  come  to  difficult  pathological  questions  we  find 


GENERAL   PATHOLOGY   OF   THE   PITUITARY     277 

the    obsession   concerning   the    duality  of  the    different   lobes   of 
the  pituitary  still  overshadowing  us. 

Thus  Cushing  states  that  hydrocephalus  may  produce  hypo- 
pituitarism from  secretory  stasis  in  the  pars  nervosa.  But  before 
this  explanation  can  be  accepted  we  must  understand  how  it  is 
that  other  tumours  in  the  neighbourhood  of  the  base  of  the 
brain  not  acting  in  the  same  way  may  produce  a  similar  train 
of  symptoms.  Further,  we  have  seen  that  neither  removal  of  the 
anterior  lobe  nor  of  the  posterior  can  produce  this  state  :  inter- 
ference with  the  whole  blood-supply  in  the  stalk  is  necessary. 
Again,  it  has  been  pointed  out — for  the  most  part  by  Cushing1 
himself — that  the  lowered  body-temperature  in  dystrophia  adiposo- 
genital! s  can  only  be  raised  by  an  extract  of  the  anterior  lobe  ; 
while  the  low  blood-pressure  can  only  be  raised,  and  the  carbo- 
hydrate-tolerance reduced,   by  an  extract  of  the  posterior  lobe. 

This  observer,  therefore,  in  one  sentence  sweeps  aside  his 
own  conclusions  and  the  conclusions  of  others  based  on  the 
assignment  of  syndromes  to  one  or  other  part  of  the  pituitary, 
instead  of  to  the  whole  organ. 

To  press  the  point  a  little  further  :  It  is  common  knowledge 
that  in  the  development  of  the  pituitary  body  the  epithelial 
structures  are  all  derived  from  the  ectoderm ;  consequently 
the  anterior  lobe  and  the  pars  intermedia  have  the  same  origin. 
From  our  histological  observations  we  know  that  the  pars  inter- 
media is  closely  related  physiologically  to  the  pars  anterior — 
so  much  so  that  the  cells  of  both  secrete  a  similar  substance. 
Further,  it  is  often  difficult  to  say  where  the  pars  intermedia 
begins  and  the  pars  anterior  ends,  for  at  the  point  of  junction  the 
cells  appear  to  change  almost  imperceptibly  from  one  type  to  the 
other.  It  has  always  been  my  opinion  that  the  active  principle  of 
the  posterior  lobe  is  secreted  by  the  cells  of  the  pars  intermedia. 
We  have  evidence,  too,  in  an  experiment  of  Vincent2,  that  an 
extract  of  the  central  portion  of  the  pars  nervosa  is  much  more 
active  in  its  pressor  effects  than  is  the  extract  made  from  the 
periphery  and  the  cells  of  the  pars  intermedia,  which  is  com- 
paratively inert.  We  have  had  evidence,  also,  that  the  secretion 
of  the  pars  intermedia  passes  into  the  pars  nervosa.  Whether 
the    secretion    passes    on    entirely    into    the    third    ventricle,    as 

1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1012. 

2  Vincent,  Swale,  The  Internal  Secretions,  1!»12. 


278     DISORDERS   ASSOCIATED   WITH  THE  PITUITARY 

described  by  Herring1  and  Cushing2,  which,  however,  I  regard  as 
doubtful,  or  whether  the  larger  portion  passes  into  the  blood- 
vessels of  the  pars  nervosa  which  are  seen  in  such  profusion  in 
the  ox  (fig.  40,  p.  62),  as  seems  most  likely,  is  of  little  import- 
ance in  regard  to  the  question  we  have  in  hand.  But  it  is  of 
considerable  importance  that  the  secretion  of  the  pars  intermedia 
does  pass  into  the  posterior  lobe  ;  and  that  the  pars  intermedia 
does  secrete  a  substance  similar  to  that  secreted  by  the  anterior 
lobe. 

It  seems  highly  probable,  therefore,  from  the  evidence  at 
our  disposal,  that  the  secretion  of  the  pars  intermedia  is  changed 
into  a  pressor  substance  as  it  passes  through  the  posterior  lobe  ; 
and  that  the  colloidal  substance  found  among  the  cells  of  the 
pars  intermedia  and  the  secretion  found  in  the  cleft  is  ot  the 
same  character  as  that  secreted  by  the  anterior  lobe.  If  this 
be  so,  we  arrive  at  the  principle  I  have  so  often  enunciated- — a 
principle  which  is  of  the  greatest  importance  in  the  interpreta- 
tion of  diseases  of  the  pituitary  body — I  mean  that  the  pituitary 
body  is  one  organ.  Much  that  is  supposed  to  be  obscure  becomes 
clear  :  for  instance,  insufficiency  of  the  hormone  from  the  pars 
nervosa  can  in  many  cases  be  accounted  for  by  insufficiency  of 
the  cells  of  the  pars  anterior  and  the  pars  intermedia,  which 
I  believe  to  be  fundamentally  the  same  physiologically  as  they 
are  anatomically.  In  these  circumstances  there  would  be  an  in- 
sufficient supply  of  secretion  to  the  pars  nervosa,  in  the  substance 
of  which  the  secretion  of  the  pars  intermedia  undergoes  altera- 
tion and  acquires  pressor  qualities.  No  pressure,  therefore,  on 
the  pars  nervosa  need  be  presumed  to  account  for  posterior  lobe 
insufficiency — a  state  of  affairs  which  can  be  relieved  by  the 
injection  of  infundibulin.  So,  too,  from  the  other  point  of  view, 
it  is  easy  to  understand  the  reason  why  in  acromegaly,  in  which 
disease  there  is  admittedly  hyperplasia  in  the  anterior  lobe,  we 
so  frequently  see  polyuria  and  glycosuria.  In  accordance  with 
the  view  just  expressed  an  excess  of  secretion  may  pass  into  the 
pars  nervosa  and  thence,  after  being  converted  into  infundibulin, 
into  the  blood. 

The    acromegaly-syndrome    may    be    summarized    from    this 
point  of  view.     Some  of  the  symptoms — the  gigantism  and  bony 

1  Herring,  P.  T.,  Quart.  Journ.  Exper.  Physiol,  1908,  i,  121. 

2  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


GENERAL   PATHOLOGY   OF   THE   PITUITARY      279 

changes  with  the  acral  enlargements,  the  coarse  skin,  the  genital 
stimulation  are  all  due  to  the  direct  influence  of  the  hyperplasia 
in  the  partes  anterior  and  intermedia.  The  polyuria  and  the 
glycosuria  are  caused  by  the  increase  in  the  amount  of  secretion 
of  the  pars  intermedia,  which  is  passed  into  the  pars  nervosa  and 
subsequently  absorbed. 

With  regard  to  the  other  condition — dystrophia  adiposo- 
genitalis — which  is  seen  with  destructive  lesions  that  impair  the 
blood-supply  and  produce  hypopituitarism,  the  entire  secretion  is 
greatly  reduced.  The  failure  of  secretion  refers  not  only  to  that 
which  is  passed  directly  into  the  blood,  but  also  that  which  is 
passed  into  the  pars  nervosa.  We  have  seen,  indeed,  that  at 
least  one  of  the  symptoms — the  subnormal  temperature — is 
relieved  by  the  extract  of  the  anterior  lobe,  and  others — namely, 
the  excessive  carbohydrate-tolerance,  and  the  low  blood-pressure 
— by  infundibulin. 

This  explanation  of  the  interrelationships  between  the  various 
portions  of  the  pituitary  body  is,  therefore,  no  idle  hypothesis. 
It  is  based  on  morphological  grounds,  on  all  the  best  of  the 
histological  work  that  has  been  done,  and  on  all  the  clinical  data 
that  are  at  our  disposal.  Practically,  it  makes  clear  many  of 
the  apparently  contradictory  features  of  hyperpituitarism  and 
hypopituitarism.  It  explains,  too,  why  with  cystic  changes  in 
the  anterior  lobe,  even  with  great  enlargement  and  sella  deforma- 
tion, the  pressure  symptoms  may  only  be  those  of  any  tumour 
in  the  interpeduncular  space- — so  long  as  normal  cells  exist  in 
sufficient  quantity  to  produce  the  necessary  secretion.  In  these 
cases,  too,  the  pars  nervosa  is  usually  crushed,  yet — provided 
there  are  normal  cells  of  the  pars  anterior,  as  I  have  just  said — 
no  intrinsic  symptoms  of  pituitary  origin  arc  evident. 

This  point  of  view — founded  on,  and  compatible  with,  all 
the  evidence  at  our  disposal — should,  if  correct,  in  the  future  do 
much  to  render  intelligible  the  pathology  of  the  pituitary  body. 


§  iv.  TREATMENT   OF   PITUITARY   LESIONS 

The    treatment     of    pituitary    disease     is     partly     medical    and 
partly  surgical. 

It  may  be  stated  that  medicinal  methods  are  only  indicated 
to  relieve  certain  metabolic  and  distant  phenomena,  and  that 
they  are  of  little  value  when  there  are  local  symptoms,  such  as 
headache  and  visual  disturbances — these  require  relief  by  surgical 
procedures. 


MEDICAL   TREATMENT    OF   PHENOMENA    DUE    TO 
PITUITARY    LESIONS 

Hypopituitarism. — Medicinal  treatment  at  the  present  time 
largely  resolves  itself  into  the  supplementation  of  the  deficient 
secretion.  No  doubt  in  a  majority  of  cases  the  best  results  are 
obtained  with  whole-gland  extracts.  Supplementary  medica- 
tion will  be  discussed  more  fully  in  connexion  with  the  thera- 
peutical uses  of  pituitary  extracts. 

It  is  extremely  difficult  permanently  to  reduce  the  sugar- 
tolerance  by  medicinal  means,  but  the  psychical  and  sexual 
disabilities  are  often  removed  :  mental  torpor  disappears  ;  men- 
struation and  potency  return. 

As  the  preparation  must  be  administered  over  a  consider- 
able length  of  time  oral  administration  is  generally  practised. 
Very  large  doses  may  be  necessary  :  dishing1  states  that  he  has 
administered  100  grains  of  whole-gland  extract  three  times  a  day. 

Glandular  administrations  are  frequently  of  value  after 
operations  for  the  relief  of  local  pressure-symptoms  in  lesions 
producing  hypopituitarism. 

I  have  observed  an  objectionable  effect  that  is  often  produced 
1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 


MEDICAL   TREATMENT   OF  PITUITARY   LESIONS     281 

by  glandular  extracts — especially  extracts  of  the  pars  anterior 
— namely,  intense  headache.  This,  however,  has  been  most 
noticeable  in  those  minor  cases  of  hypopituitarism,  in  which 
amenorrhcea  was  the  only  obvious  symptom. 

Cushing  found  in  one  case  after  the  failure  of  oral  adminis- 
trations that  daily  hypodermic  injections  of  whole-gland  extract, 
in  a  dose  representing  2  grains  of  the  dried  extract,  produced 
an  amazing  effect  in  regard  to  the  mental  and  physical  vigour  of 
the  patient. 

In  the  same  patient  a  graft  from  the  pituitary  of  a  child  dying 
in  child-birth  was  subsequently  implanted  in  the  subcortical 
tissues  of  the  temporal  lobe  with  permanent  benefit,  in  spite  of 
the  discontinuance  of  hypodermic  medication. 

Hyperpituitarism.  -The  medicinal  treatment  of  this  con- 
dition is  not  satisfactory,  except  in  the  presence  of  a  plurigland- 
ular syndrome  which  beckons  unmistakably  to  the  extracts  of 
the  organs  whose  secretion  is  diminished. 

Thyroid  extract  has,  however,  often  been  given  with 
advantage,  especially  in  cases  of  arrested  acromegaly. 

Kelladey1  records  a  case  of  acromegaly  in  a  woman,  in  whom 
intravenous  injections  of  ovarian  extract  induced  the  return  of 
menstruation  with  subsequent  conception. 

1  Kelladey,  L.,  Zentralbl.  /.  Gynak.,  1913,  xxxvii,  1030. 


SURGICAL    TREATMENT    OF    PITUITARY    LESIONS 


SURGICAL    ANATOMY 

We  have  seen  that  the  modern  experimental  procedures  designed 
for  the  removal  of  the  whole  or  of  part  of  the  pituitary  are 
not  difficult  to  carry  out  by  the  intracranial  (bitemporal)  route 
in  the  case  of  dogs  owing  to  the  fact  that  in  this  animal,  which 
is  also  of  a  fair  size,  the  organ  rests  in  a  very  shallow  fossa  ;  but 
that  in  an  animal,  such  as  the  cat,  in  which  the  pituitary  fossa 
is  deep,  the  intracranial  method  is  impracticable.  Further,  we 
have  seen  that  the  buccal  route  is  invariably  unsatisfactory 
because  the  operator  cannot  control  by  sight  his  manipulations 
in  regard  to  the  pituitary,  and  in  any  case  he  cannot  do 
more  than  blindly  destroy  the  whole  structure  or  remove  a 
portion  of  the  pars  anterior,  and  because  there  is,  also,  an  almost 
inevitable  risk  of  sepsis  from  the  buccal  cavity,  with  fatal  mening- 
itis. Thus  it  has  come  about  that  no  experimental  results 
obtained  by  operative  procedures  have  been  found  worthy  of 
acceptance,  except  when  they  have  been  practised  on  one 
species  of  animal  (dog),  and  by  the  route  of  election  (bitemporal) 
in  that  animal. 

It  will  readily  be  realized,  then,  that  in  man,  in  whom  the 
pituitary  is  situated  in  a  deep  fossa,  which  is  closely  guarded 
on  every  side  by  nerves,  arteries  and  large  venous  channels, 
suitable  access  has  been  found  difficult  to  obtain.  As  a  result, 
many  different  directions  have  been  chosen  by  surgeons  for 
attacking  pituitary  lesions  in  the  human  subject  (fig.  179). 
These  various  routes  will  be  discussed  presently,  but  before  we 
consider  them  in  detail  it  will  be  worth  while  to  study  a  few 
details  of  the  surgical  anatomy  of  the  parts. 

First,  when  the  temporal  route  is  chosen  it  should  be  re- 
membered that  the  temporal  lobe  is  situated  in  a  deep  concave 


SURGICAL   ANATOMY 


283 


fossa,  and  that  the  brain  must  be  raised  before  the  edge  of  the 
sella  turcica  can  be  reached  ;  and  further,  that  when  the  sella  is 
reached  the  pituitary  disease  cannot  be  attacked  owing  to  the 
depth  of  the  fossa  unless  the  lesion  extend  upwards. 

Second,  with  regard  to  the  frontal  intracranial  route,  it 
will  be  evident  that  when  the  frontal  lobes  are  to  be  raised  the 
success  of  the  operation  will  depend  greatly  on  the  production 
of    a    low    intracranial    pressure,    and    that    by    this    route    it   is 


Fig.  179. 

Incisions  (shown  by  dotted  lines)  for  the  various  procedures  that  have  been 
adopted,  a,  Horsley-Paul  temporal  method  ;  b,  Frazier  orbitofrontal  method  ; 
c,  Eiselsberg  first  superior  nasal  method ;  d,  Eiselsberg  second  superior  nasal 
method ;  e,  Schloffer-Eiselsberg  superior  nasal  method ;  /,  Kanavel  inferior  nasal 
method ;  g,  Halstead-Cushing  sublabial  method ;  h,  Chiari-Kahler  orbitonasal 
method. 


impossible    satisfactorily  to    deal  with    a    pituitary   lesion    that 
does  not  extend  upwards. 

Third,  with  respect  to  the  nasal  routes,  we  shall  see  that 
some  are  much  better  than  others  owing  to  the  differences  in 
regard  to  the  possibility  of  minimizing  the  risk  of  sepsis  and 
the  degree  of  mutilation  inflicted.  But  the  operative  procedures 
by  this  route  are  not  always  easy  because  of  the  variations  that 
may  occur  in  the  anatomy  of  the  parts. 


284     DISORDERS   ASSOCIATED   WITH  THE  PITUITARY 

With  this  difficulty  in  mind,  Gibson1  has  made  a  careful 
investigation  of  the  principal  measurements  in  relation  to  the 
pituitary  fossa  in  107  skulls,  apparently  without  distinction  as  to 
sex.  He  also  paid  particular  attention  to  the  character  of  the 
sphenoidal  sinuses  and  to  the  floor  of  the  sella  turcica.  Cope2, 
too,  has  recently  studied  these  questions,  also  without  regard 
to  sex. 

Although  no  doubt  surgeons  with  large  experience  in 
operations  on  the  pituitary  by  the  nasal  route— of  whom  there 
are  at  present  only  a  few- — are  able  to  accommodate  themselves 
to  the  varying  circumstances,  Gibson's  and  Cope's  figures  and 
observations  are  of  considerable  value  to  the  less  experienced 
operator.  At  the  same  time,  the  fact  has  not  been  adequately 
emphasized  by  these  writers  that  pituitary  lesions  by  pressure 
and  extension  downwards  may  alter  considerably  the  character 
of  the  floor  of  the  sella  turcica,  and  the  relation  of  it  to  the 
sphenoidal  cells. 

Gibson  gives  the  following  average  measurements  (fractions 
omitted),  which,  with  very  few  exceptions  in  regard  to  the 
larger  measurements,  were  found  not  to  vary  to  the  extent  of 
one  centimetre  : — 

Nasion  to  sella  turcica3 62  mm. 

Nasion  to  posterior  surface  of  sella  turcica  .       .      .    75  mm. 

Anterior  nasal  spine  to  sella  turcica4 78  mm. 

Anterior  nasal  spine  to  clivus 88  mm. 

Length  of  the  pituitary  fossa         ......    12  mm. 

Depth  of  the  pituitary  fossa 6  mm. 

Depth  of  the  sphenoidal  sinus  on  the  line  from  the 

anterior  nasal  spine  to  the  sella  turcica     .      .      .18  mm. 

These  and  other  measurements  are  shown  in  figure  180; 
but  fractions  have  been  omitted. 

With  regard  to  the  variations  in  the  sphenoidal  sinuses,  which 
are  illustrated  in  figure  14  (p.  23),  Gibson  gives  the  following 
particulars. 

Complete  or  practical  absence  of  sinuses  (fig.  14,  b)  occurs  in 

1  Gibson,  W.  S.,  Surg.  Gynecol.  Obstet.,  1912,  xv,  199. 

2  Cope,  V.  Z.,  Brit  Journ.  Surg.,  1916,  iv,  107. 

3  Cope  (he.  cit.)  found  the  average  of  this  measurement  to  be  604  mm. 

4  Cope  (loc.  cit.)  found  the  average  of  this  measurement  to  be  76-19  mm. 


SURGICAL    ANATOMY 


285 


3  per  cent.  ;  small  sphenoidal  sinuses  in  9  per  cent. ;  no  projection 
of  sinuses  beneath  the  sella  turcica  (fig.  14,  d)  in  22  per  cent,  of 
all  cases  examined.  The  fact  that  in  these  variations  the  floor 
of  the  sella  does  not  bulge  into  the  sphenoidal  sinuses  might 
cause  difficulty  in  the  determination  of  its  position.  He  also 
found  that  in  2  per  cent,  of  the  cases  there  was  a  transverse 
sphenoidal  septum  (fig.  14,  e),  which  might  be  mistaken  for  the 
roof  of  the  sinuses. 

When  the  sphenoidal  sinuses  project  beneath  the  sella  tur- 
cica, and  have  thin  posterior  walls  (fig.  14,  c),  these  may  be 
pierced  by  the  operator,  and  the  pons  injured. 


Fig    180. 

Sectional  measurements  of  the  skull  in  relation  to  the  sella  turcica  and 
sphenoidal  sinuses.  The  figures  are  accurate,  but  the  skull  is  reduced  approxim- 
ately by  one-half. 


Besides  these  vagaries  the  cribriform  plate  may  dip  down 
unduly,  and,  by  obscuring  the  direct  line  of  attack,  cause  the 
operator  to  divert  his  course  below  the  sella  turcica ;  or  a 
deflected  septum  may  cause  him  to  miss  the  correct  median 
approach. 


286     DISORDERS   ASSOCIATED    WITH  THE  PITUITARY 


INDICATIONS    FOR    OPERATION 

The  following  symptoms  demanding  interference  must  be  shown 
to  he  dependent  on  enlargement  of  the  pituitary,  or  on  lesions  situ- 
ated in  the  neighbourhood  of,  and  affecting,  the  pituitary. 

(a)  Symptoms  due  to  increased  general  intracranial  pressure, 
such  as  headache. 

(b)  Symptoms  due  to  local  pressure,  such  as  blindness,  oculo- 
motor palsy  and  '  pituitary  headache  '. 

(c)  Symptoms  due  to  disturbances  of  the  pituitary  secretion 
producing  acromegaly  or  dystrophia  adiposogenital . 


SELECTION    OF    THE    ROUTE    OF    APPROACH 

The  method  adopted  for  approaching  the  pituitary  should 
depend,  to  a  great  extent,  on  the  special  reason  for  operation. 
Thus,  general  intracranial  pressure  must  be  relieved  by  an  intra- 
cranial method,  whereas  the  relief  of  '  pituitary  headache  '  and 
the  evacuation  of  pituitary  cysts  are  better  effected  by  the  nasal 
route  ;  consequently  an  accurate  diagnosis  of  the  condition  present 
is  the  first  step  in  the  selection  of  a  route  by  which  the  lesion 
may  be  reached  and  the  symptoms  relieved.  The  direction 
of  extension  of  the  lesion  may,  too,  be  a  matter  of  importance. 
To  a  certain  extent,  also,  the  surgeon  should  be  influenced  in 
his  choice  of  direction  by  the  anatomical  conformation  of  the 
sphenoid  and  sphenoidal  sinuses.  A  good  radiograph  conveys 
the  necessary  information  in  regard  to  this  matter. 

In  spite  of  these  associations  which  should  guide  the  surgeon 
in  the  selection  of  a  method  of  approach,  it  appears  that  most 
operators  have  a  route  of  election  for  every  case.  Schloffer1, 
Proust2,  Cushing3,  and  more  recently  Cope4,  have  discussed  the 
subject,  but  it  is  evident  that  no  final  decision  has  yet  been 
reached  as  to  the  indications  for  the  different  routes. 

1  Schloffer,  H.,  Beitr.  z.  Klin.  Chir.,  1906, 1,  767. 

2  Proust,  R.,  Journ.  de  Chir.,  1908,  i,  665. 

3  Cushing,   PL,   The  Pituitary   Body  and  its  Disorders,    1912 ;     Weir  Mitchell 
Lecture :  Journ.  Amer.  Med.  Assoc,  1914,  lxiii,  1515. 

4  Cope,  V.  Z.,  Brit.  Journ.  Surg.,  1916,  iv,  107. 


SURGICAL   TREATMENT 


287 


PREPARATION    OF    THE    PATIENT 

In  all  operations  on  the  pituitary  hexamethylenamine  (fora- 
mine)  should  be  administered  for  some  days  before  and  after 
operation  to  render  the  cerebrospinal  fluid  antiseptic  (see  p.  129). 

Lumbar  puncture  as  a  preliminary  operative  procedure  is 
extremely  useful  for  reducing  the  intracranial  pressure  if  more 
than  decompression    is    to   be   attempted.     Moreover,   the    over- 


Fig.  181. 

Base  of  the  skull,  showing  the  directions  followed  in  the  intracranial 
methods  of  approach  to  the  sella  turcica.     (Photograph.) 

hanging-brain  position  (fig.  184,  p.  295)  suggested  by  Karplus  and 
Kreidl1,  may  be  used  to  facilitate  the  surgical  manipulations. 
The  other  general   preparations   need   no   special  description. 

INTRACRANIAL    METHODS 

Two  directions  have  been  chosen  for  reaching  the  pituitary 
intracranially  in  the  human  subject — the  temporal  and  the  fronto- 
orbital  (fig.  181). 

1  Karplus,  J.  P.,  and  A.  Kreidl,  Wien.  Klin.  Woch.,  1910,  xxiii,  309. 


288     DISORDERS    ASSOCIATED    WITH  THE  PITUITARY 


Temporal  and  bitemporal  routes 

The  actual  procedures  in  regard  to  this  operation  on  the 
human  subject  need  not  be  recapitulated,  for  they  correspond 
almost  exactly  with  those  which  have  been  adopted  in  experi- 
mental operations  on  animals,  and  have  already  been  fully 
described  and  illustrated  (p.  129  and  following). 

This  method  of  approach,  as  emphasized  by  Gushing1,  is 
unquestionably  the  best  for  the  relief  of  general  intracranial 
pressure  ;  indeed,  this  surgeon  advises  that  a  temporal  decom- 
pression operation  should  always  be  performed  when  the  intra- 
cranial pressure  is  great,  even  though  it  be  thought  advisable 
subsequently  to  attack  the  actual  lesion  by  another  route,  for  in 
those  cases  in  which  headache  is  very  severe,  and  is  associated 
with  a  choked  optic  disc,  superimposed  on  optic  atrophy,  a 
pituitary  tumour  is  generally  present  and  is  extending  upwards. 
It  must  be  remembered  that  the  so-called  '  pituitary  headache  ' 
differs  from  the  headache  associated  with  general  intracranial 
pressure  in  that  it  is  caused  by  local  pressure  in  the  pituitary  fossa. 

As  a  method  of  approach  for  operations  on  the  pituitary  in 
the  human  subject  the  temporal  (fig.  179,  a)  has  not  secured  much 
favour.  It  was  originally  suggested  by  Horsley2  as  the  result 
of  his  experimental  experiences,  and  Paul3  was  the  first  to  employ 
the  procedure  in  the  human  subject.  Paul's  operation — the  first 
undertaken  for  pituitary  disease — was  attempted  for  the  relief 
of  severe  headache  in  a  case  of  acromegaly  under  the  care  of 
Caton  in  the  Liverpool  Royal  Infirmary  on  February  2nd,  1893. 
The  operation  was  not  carried  further  than  simple  decom- 
pression, by  the  removal  of  a  portion  of  the  temporal  bone.  The 
headaches  were  relieved,  and  the  patient  lived  for  three  months 
subsequently.  Henceforth,  the  possibilities  of  surgical  pro- 
cedures came  to  be  fully  recognized,  and  Horsley  himself  per- 
formed operations  on  the  human  subject  by  the  same  route. 
The  details  of  his  results  were  never  published,  but  so  far  as  is 
known  they  were  not  satisfactory. 

Cushing1,    too,     has     performed     a    few    operations    on     the 

1  Cushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Horsley,  V.,  Lancet,  1886,  i,  5. 

3  Paul,  F.  T.,  and  R.  Caton,  Brit.  Med.  Journ.,  1893,  ii,  1421. 


SURGICAL   TREATMENT  289 

pituitary  by  the  temporal  route — apart  from  simple  decom- 
pression measures — and  he  has  come  to  the  conclusion  that 
this  method  should  not  be  the  one  of  election  for  dealing  with 
pituitary  growths  in  general.  He  states  that  in  the  entire  series 
of  his  cases,  as  published  in  his  book,  "  in  only  one  patient  .  .  . 
did"  post-mortem  study  indicate  that  a  lateral  subtemporal 
operation  would  have  offered  the  only  chance  of  surgical  relief  "1. 
This  case  was  one  in  which  there  was  an  infundibular  cyst  situated 
above  an  otherwise  normal  pituitary.  The  only  symptom  was 
bitemporal  hemianopia.  The  patient  died  from  meningitis  on 
the  thirteenth  day  after  an  attempted  transphenoidal  operation. 

Orbitofrontal  route 

This  method  of  approach,  originally  put  forward  by  Krause2 
and  McArthur3,  and  perfected  by  Frazier4,  has  lately  received 
considerable  support,  and  was  utilized  by  Cope5  in  the  three 
operations  performed  by  him.  Erdmann6  and  Elsberg7,  also, 
have  employed  this  method  with  slight  modifications.  The 
technique  of  Frazier's  operation  is  as  follows. 

The  patient  is  anaesthetized  with  ether — first  by  the  open,  and 
afterwards,  when  anaesthesia  is  complete,  by  the  intratracheal 
method.  He  is  then  placed  with  the  shoulders  on  a  pillow 
over  the  top  of  which  the  head  is  allowed  to  fall  back  (over- 
hanging-brain  position),  and  the  frontal  sinuses  are  transillumin- 
ated  to  show  their  size.  Next,  an  incision  is  made  extending 
along  the  supraorbital  ridge  from  the  external  angular  process  to 
the  nasion  ;  from  this  point  the  incision  is  carried  vertically  up 
wards  beyond  the  hair-line  almost  to  the  summit  of  the  fronto- 
parietal suture,  and  then  outwards  at  right  angles  over  the  frontal 
bone  till  a  point  is  reached  vertically  above  the  external  angular 
process  where  the  skin-incision  was  commenced  (figs.  179,  b  and 
182).      The   skin,   subcutaneous   and  pericranial   tissues   are   now 

1  Gushing,  H.,  The  Pituitary  Body  and  its  Disorders,  1912. 

2  Krause,  F.,  Deutsch.  Klin.,  1905,  viii,  1004. 

3  McArthur,  L.  L.,  Journ.  Amer.  Med.  Assoc,  1912,  lviii,  2009. 

4  Frazier,  C.  H.,  Ann.  Surg.,  1913,  lvii,  145  ;    Surg.  Gynaecol,  and  Obstet.,  1913, 
xvii,  724. 

5  Cope,  V.  Z.,  Brit.  Journ.  Surg.,  1916,  iv,  107. 

6  Erdmann,  J.  F.,  Ann.  Surg.,  1914,  hx,  452. 

7  Elsberg,  C.  A.,  Ann.  Surg.,  1914,  lix,  454. 

19 


290     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

retracted  far  enough  to  permit  the  formation  of  an  osteoplastic 
flap  which  is  turned  outwards  after  the  bone  has  been  cut  through 
by  means  of  a  trephine  and  wire-saw.  The  periosteum  of  the  roof 
of  the  orbit  is  separated,  and  the  supraorbital  ridge  is  divided 
by  means  of  converging  incisions,  in  order  that  a  wedge-shaped 
piece  of  bone  may  be  removed  (fig.  182),  which  will  fall  into 
position    on   replacement   without   the    need   of    fixation.      With 


Fig.  182. 
Fraziers  orbitofrontal  method  of  approach  to  the  pituitary.     (After  Frazier.) 

this  piece  of  the  ridge  the  anterior  portion  of  the  roof  of  the 
orbit  is  resected.  The  posterior  part  of  the  orbital  roof  as  far 
back  as  the  optic  foramen  is  now  removed  with  a  rongeur. 

This  exposure  permits  the  operator  to  displace  the  orbital 
contents  downwards  and  outwards,  and  to  raise  the  frontal  lobe 
without  opening  the  dura  mater.  If,  however,  the  intracranial 
tension  be  great  and  a  preliminary  lumbar  puncture  have  not 
been  performed,  a  small  opening  may  be  made  in  the  dura  to 


SURGICAL   TREATMENT  291 

allow  the  cerebrospinal  fluid  to  escape.  The  frontal  lobe  is  then 
raised  with  a  retractor — preferably  spoon-shaped  (fig.  87,  p.  135) 
— until  the  optic  nerve  is  seen  leaving  the  cranial  cavity  ;  at 
this  point  the  dura  is  incised  and  the  retractor  slipped  through 
the  opening  thus  made  in  order  that  the  pituitary  region  may 
be  fully  exposed. 

At  the  conclusion  of  the  operation  the  supraorbital  fragment 
is  replaced  and  the  osteoplastic  flap  sutured  in  position. 

It  is  claimed  that  by  this  route  suprasellar  lesions  can  easily 
be  attacked,  and  the  general  intracranial  pressure  relieved.  The 
orbitofrontal  competes,  therefore,  with  the  temporal  method. 

EXTRACRANIAL    METHODS 

Nasal  (transphenoidal)  routes 

Schloffer1  first  suggested  reaching  the  pituitary  by  way  of 
a  nasal  route.  The  interest  aroused  by  this  method  of  procedure 
is  shown  by  the  enthusiasm  with  which  it  has  been  adopted  and 
modified  (fig.  183).  The  technique  of  these  operations  may  be 
described  under  two  headings. 

Superior  nasal  methods.  -This  route,  which  was  origin- 
ally advocated  by  Schloffer1,  if  we  except  the  experimental 
nasofrontal  operation  of  Giordano2,  has  been  employed  chiefly 
by  von  Eiselsberg3.  The  operation  was  at  first  performed  by 
this  operator  in  the  following  manner. 

The  posterior  nares  were  packed  to  prevent  the  inhalation 
of  blood.  One  incision  through  the  skin  was  made  across  the 
brows  bilaterally,  and  another,  which  joined  the  first  incision  at 
the  root  of  the  nose  on  the  left  side,  was  carried  down  the  side 
of  the  nose  and  along  the  nasolabial  furrow  beneath  the  left 
nostril  to  the  mid-line  (fig.  179,  c). 

The  nasal  bones  were  cut  through  with  a  chisel.  The  septum 
--  cartilaginous  and  bony — was  then  divided  in  such  a  way  as 
to  leave  a  large  portion  of  the  cartilage,  ethmoidal  plate  and 
vomer  to  be  turned  over  with  the  nose  to  the  right  side.     This 

1  Schloffer,  H.,  Beitr.  z.  Klin.  Chir.,  1906,  1,  767. 

2  Giordano,  D.,  Comp.  di  Chir.  Operat.  Hal,  1897,  ii,  100. 

3  Eiselsberg,  F.  von,  Trans.  Amer.  Svrg.  Assoc,  1910,  xxviii,  55 ;  Ann.  Surg., 
1910,  lii,  1  ;   Arch.f.  Klin.  Chir.,  1912,  c.  8. 


292     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

precaution  retained  subsequently  a  good  '  bridge  '  for  the  nose. 
Next,  the  anterior  wall  of  the  frontal  sinuses  was  raised  through 
the  transverse  incision.  The  turbinate  bones  and  ethmoidal 
cells  were  excised,  and  the  operator  then  came  down  upon  the 
anterior  wall  of  the  sphenoidal  sinus.  This  and  the  anterior 
wall  of  the  floor  of  the  sella  turcica  were  removed  and  the  pituitary 
exposed.  Later,  Eiselsberg1  performed  much  the  same  operation 
after  making  a  slightly  different  incision  (fig.  179,  d)  and,  later 
still,  by  turning  back   the  nose  alone   without    interfering   with 


Fig.   183. 

Vertical  section  through  the  skull,  showing  the  direction  of  the  chief  routes  by 
which  the  pituitary  has  been  attacked  from  the  front.  A,  Orbitofrontal  route ; 
B  and  C,  superior  nasal  routes ;  D,  inferior  nasal  route  ;  E,  buccal  route. 

the    frontal     sinuses.     This    last    procedure    has,    however,    been 
attributed  to  Schloffer  (fig.  179,  e). 

These  methods  are  unnecessarily  mutilating  and  have  been 
discarded  in  favour  of  the  submucous  inferior  nasal  procedures. 

Inferior  nasal  methods. — Kanavel2  was  the  first  to  show 
that  it  is  possible  to  reach  the  pituitary  fossa  through  the  inferior 
nasal  route.  By  this  method  the  nose  was  turned  upwards  by 
means    of    a     U-shaped    incision    which    divided    the    nasolabial 

1  Eiselsberg.  F.  von,  Arch.  /.  Klin.  Chir.,  1912,  c,  8. 

2  Kanavel,  A.  B.,  Journ.  Amer.  Med.  Assoc,  1909,  liii,  1704. 


SURGICAL   TREATMENT  293 

junction  (fig.  179,  /).  The  cartilaginous  septum  was  divided 
along  the  inferior  border,  and  was  partly  raised  and  partly  cut 
away  from  its  attachment  to  the  ethmoidal  plate.  Next,  the 
middle  turbinates  were  removed  and  the  septum  was  deflected 
to  one  side.  The  anterior  walls  of  the  sphenoidal  sinuses  were 
then  excised  and  the  floor  of  the  sella  turcica  was  cut  through. 

Mixter  and  Quackenboss1,  who  employed  this  route  subseq- 
uently in  the  case  of  a  pituitary  tumour  in  a  child,  made  the 
important  modification  of  submucous  resection  of  the  septum — 
a  procedure  that  lessened  considerably  the  risk  of  sepsis. 

Hirsch2,  basing  his  procedures  on  Hajek's3  radical  operation 
on  the  sphenoidal  sinuses,  modified  the  method  by  performing 
the  operation  through  one  nostril.  The  procedures  were  com- 
pleted in  several  sittings.  In  the  earlier  steps  the  nasal  septum, 
the  middle  turbinates  and  the  ethmoidal  cells,  were  excised,  and 
the  sphenoidal  sinuses  laid  open  ;  subsequently,  the  anterior  wall 
of  the  floor  of  the  sella  turcica  was  removed,  and  the  pituitary 
attacked.  These  procedures  were  all  carried  out  under  local 
anaesthesia.  Later  Hirsch4  recommended  the  same  operation 
with  submucous  resection  of  the  septum. 

Halstead5,  also,  modified  the  original  method  of  Kanavel  by 
gaining  access  to  the  nasal  cavity  by  means  of  a  sublabial 
incision  (fig.  179,  g).  The  upper  lip  and  nose  were  raised  and 
the  operation  was  performed  through  the  aperture  into  the  nares 
so  created. 

These  modifications  led  to  the  perfected  technique — now 
practised  by  Gushing6  and  others — which  appears  to  be  the  best 
of  all  the  nasal  methods,  combining  as  it  does  the  principal  ad- 
vantages of  several  of  the  intranasal  route  procedures.  Since 
this  method  is  likely  to  be  used  extensively,  the  following  par- 
ticulars of  the  technique  are  worth  recording. 

After  undergoing  preliminary  treatment  for  a  few  days  with 
f ormamine  the  patient  is  anaesthetized  with  ether  by  the  *  open  ' 

1  Mixter,  S.  J.,  and  A.  Quackenboss,  Ann.  Surg.,  1910,  Hi,  15 ;  Trans.  Amer. 
Surg.  Soc,  1910,  xxviii,  94. 

2  Hirsch,  O.,  Wien.  Med.  Woch.,  1909,  lix,  G3G. 

3  Hajek,  M.,  Arch.  f.  Laryngol.  und  Rhinol,  1904,  xvi,  105. 

4  Hirsch   O.,  Journ.  Amer.  Med,  Assoc,  1910,  lv,  772. 

5  Halstead,  A.  E.,  Trans.  Amer.  Surg.  Assoc,  1910,  xxviii,  73. 

6  Cushing,  H.,  Weir  Mitchell  Lecture:  Journ.  Amer.  Med,  Assoc,  1914,  lxiii, 
1515. 


294     DISORDERS   ASSOCIATED   WITH   THE   PITUITARY 

method.      As    soon    as    anaesthesia    is    complete    this    mode     of 
administration  is  changed  for  the  intratracheal  method. 

The  patient  is  placed  in  the  overhanging-brain  position.  The 
operator  stands  leaning  over  the  top  of  the  head. 

First,  the  upper  lip  is  pulled  towards  the  surgeon  and  an 
incision  an  inch  in  length  is  made  through  the  frsenum,  as 
suggested  by  Halstead.  The  lip  and  nose  are  retracted  as 
the  incision  is  carried  down  to  the  anterior  nasal  spine  of  the 
superior  maxilla  (fig.  184).  Blunt  dissection  is  employed  to  raise 
the  soft  tissues  from  the  bony  floors  of  the  nasal  cavities,  and 
from  the  lower  lateral  aspects  of  the  septum,  great  care  being 
taken  lest  the  mucosa  be  button-holed.  Retractors  with  blades 
6  cm.  in  length  and  1*8  cm.  in  width  are  now  inserted  on  either 
side  to  keep  back  the  mucous  membrane  set  free  from  the  septum 
and  inner  aspects  of  the  floors  of  the  nasal  cavities  (fig.  185). 
Next,  a  strip  of  cartilage,  the  lower  edge  of  the  plate  of  the  eth- 
moid, and  a  large  portion  of  the  vomer  are  cut  away.  A  special 
dilator  is  then  pushed  into  the  cavity  thus  made  while  the  lateral 
retractors  are  still  maintained  in  position.  By  this  means  the 
turbinates  are  temporarily  flattened  and  room  is  obtained  for  the 
subsequent  steps  of  the  operation.  The  lateral  retractors  are 
now  removed  and  a  suitable  bivalve  nasal  speculum  is  inserted 
(fig.  186).  With  this  in  place,  and  by  the  use  of  a  head-lamp, 
the  sphenoidal  attachment  of  the  septum  can  be  identified,  and 
the  sphenoidal  sinuses  opened  by  means  of  a  nasal  ronguer  (fig. 
186). 

So  far  the  principal  danger  has  been  lest  the  orientation  should 
not  have  been  properly  determined,  and  the  ethmoidal  cells 
have  been  opened  instead  of  the  sphenoidal.  This  can  be  avoided 
by  recognition  of  the  posterior  margin  of  the  vomer,  and  by 
careful  examination  of  the  radiograph  taken  before  operation, 
which  should  show  the  size  and  the  relationships  of  the  ethmoidal 
and  sphenoidal  sinuses.  During  the  whole  course  of  the  opera- 
tion it  is  absolutely  imperative  that  the  field  be  kept  free  of 
blood. 

When  the  anterior  and  lower  walls  of  the  sphenoidal 
sinuses  and  their  mucous  linings  have  been  removed,  the  roof 
is  easily  identified.  Usually  it  is  thin,  and  it  may  so  bulge 
forwards  from  the  pressure  in  the  sella  turcica  above  as  practically 
to   occlude   the   sphenoidal    sinuses.      The   thin    lamina   of   bone 


SURGICAL   TREATMENT 


295 


Fig.  184. 

Partly  sectional  view  of  the  first  stage  of  the  submucous  inferior  nasal  method 
of  approach  to  the  pituitary  (P).     {After  Gushing.) 


296     DISORDERS   ASSOCIATED  WITH    THE   PITUITARY 

forming  the  roof  of  the  sinuses  and  floor  of  the  sella  turcica  is 
cut  through,  and  the  dura  mater  lining  the  fossa  is  incised  with  a 
hooked  knife  similar  to  that  employed  in  experimental  operations 
(fig.  88,  p.  130).     In  this  last  stage  some  care  is  necessary  lest  a 


Fig.  185. 

Second  stage  of  the  submucous  inferior  nasal  method  of  approach  to 
the  pituitary.     (After  Gushing.) 

transverse  sphenoidal  septum  be  mistaken  for  the  floor  of  the 
sella  turcica.  A  good  radiograph  of  the  region  should,  however, 
reveal  such  an  anomaly. 

The  pituitary  is  now  exposed,  and  the  operator  can  deal  with 


SURGICAL   TREATMENT 


297 


it  as  may  be  considered  necessary.  In  some  cases,  in  which 
relief  from  '  pituitary  headache  '  is  the  object  of  the  operation, 
nothing  further  is  done — a  sella  decompression  has  been  accom- 
plished. In  other  cases  a  cyst  may  be  evacuated  or  a  portion 
of  a  hyperplastic  gland  removed  for  the  relief  of  symptoms 
occurring  in  acromegaly. 


Fig.  186. 

Third  and  fourth  stages  of  the  submucous  inferior  nasal  method  of  approach 
to  the  pituitary.      (After  Gushing.) 

At  the  conclusion  of  these  procedures,  after  the  operator 
has  ascertained  that  there  is  no  oozing  of  blood,  the  speculum  is 
withdrawn  and  the  parts  are  allowed  to  fall  together.  Two  or 
three  stitches  are  then  used  to  close  the  initial  sublabial  incision. 
It  is  advisable  lightly  to  pack  the  nares  for  a  few  hours  in  order 
to  keep  the  septal  mucosa  in  position  and  to  prevent  the  accumul- 
ation of  blood  in  potential  spaces. 

With  regard  to  these  operations  by  the  nasal  route  it  may  be 


298     DISORDERS   ASSOCIATED  WITH   THE   PITUITARY 

said  that  only  those  procedures  which  are  performed  by  the 
submucous  methods  can  be  conducted  with  any  pretence  of 
asepsis.  Practically  all  the  cases  that  are  lost  die  from  meningitis. 
Cushing's  latest  mortality  figures  are,  however,  so  excellent  that 
there  can  be  little  doubt  that  in  suitable  cases  this  is  the  safest 
and  most  convenient  operation. 

Orbital  and  orbitonasal  routes 

In  1910  I  attempted  experimentally  to  reach  the  pituitary 
through  the  orbit1,  after  excision  or  displacement  of  the  eye,  and 
removal  of  the  posterosuperior  bony  wall  of  the  orbit.  Owing 
to  the  limited  space  in  small  animals  it  was  not  found  to  be  a 
suitable  experimental  procedure. 

Kahler2  has  employed  in  the  human  subject  a  paranasal 
operation  in  which  a  curvilinear  incision  is  made  around  the 
inner  aspect  of  the  orbit  (fig.  179,  h),  and  the  eye  retracted  out- 
wards. To  some  extent  there  is  encroachment  upon  the  nasal 
cavity,  and  this  renders  sepsis  likely,  although  there  is  less 
danger  than  in  the  operation  of  a  similar  nature  practised  by 
Chiari3  who  removes  the  inner  wall  of  the  orbit  and  clears 
away  the  neighbouring  ethmoidal  cells. 

Buccopharangeal  route 

Early  investigators  employed  the  buccal  method  of  approach 
in  their  animal  experiments  ;  but,  partly  owing  to  the  frequent 
occurrence  of  sepsis  and  partly  because  of  the  limited  view,  these 
investigations  have  been  held  to  be  of  little  value. 

It  is,  therefore,  somewhat  surprising  to  find  that  this  method 
has  been  advocated  for  reaching  the  human  pituitary  in  operative 
procedures.  Konig4  has  described  an  operation  of  this  nature. 
The  soft  palate  is  split,  and  a  portion  of  the  hard  palate  removed 
(fig.  183  e).  In  this  way  the  base  of  the  sphenoid  is  reached 
and  the  sella  turcica  opened. 

The  almost  inevitable  sepsis  that  must  follow  such  a  pro- 
cedure renders  its  general  adoption  extremely  unlikely,  especially 

1  Bell,  W.  Blair,  Hunterian  Dissertation,  Roy.  Coll.  Surg.,  Eng.,  1912. 

2  Kahler  (quoted  by  von  Szily,  Klin.  Monats.  /.  Augenheil,  1914,  lii,  202). 

3  Chiari,  O.,  Wien.  Klin.  Woch.,  1912,  xxv,  5. 

4  Konig,  F.,  Bed.  Klin.  Woch.,  1900,  xxxvii,  1040. 


SURGICAL   TREATMENT 


299 


in  view  of  the  fact  that  there  are  much  safer  and  more  suitable 
methods  of  approach. 


RESULTS    OF    OPERATIONS 

Cope1  has  collected  the  results  of  the  principal  operators 
with  a  view  to  determining  which  procedure  has  the  least 
mortality.  Naturally,  there  is  an  element  of  uncertainty  that 
obtains  in  any  such  series,  both  in  regard  to  the  seriousness  of  the 
cases  attacked  and  to  the  skill  and  experience  of  the  operator. 
One  fact  stands  out  clearly,  however,  and  that  is  that  up  to  the 
present  time  the  benefit  derived  from  operation  has  rarely  been 
permanent.  Nevertheless,  there  is  ample  evidence  to  encourage 
surgeons  to  operate  more  frequently  for  pituitary  disease. 

From  the  following  table,  adapted  from  Cope's  paper,  it  will 
be  obvious  that  the  palatal  operation  should  never  be  attempted, 
while  the  orbitonasal  procedure  in  a  limited  number  of  cases 
was  free  from  mortality.  But,  on  the  other  hand,  we  have  in- 
sufficient information  to  tell  us  by  which  measure  the  greatest 
ultimate  good  can  be  accomplished  so  far  as  relief  of  symptoms 
is  concerned. 


Table  XII 


Method. 

Operators. 

Number  of 
operations. 

Deaths. 

Mortality  per 
cent. 

Superior  nasal 

von  Eiselsberg 

10 

4 

25 

Inferior  nasal 

,,            ,,    Submucous 

Hirsch 
Gushing 

106°}'32 

> 

9 

Temporal        .... 

/Horsley 
1  Gushing 

"»« 

l)> 

11 

i  Frazier 

41 

°) 

Orbitofrontal 

I  Gushing 
j  Sargent 

»\m 

!« 

77 

vCope 

3  J 

oJ 

Orbitonasal    .... 

/Kahler 
'Ghiari 

\\  • 

U}» 

0 

Preysing 

6 

4 

66 

It  is  obvious  that  in  the  future  the  benefits  that  will  accrue 
from  surgical  interference  will  be  directly  proportional  to  the 
correct  application  of  the  most  suitable  method  to  the  particular 


1  Cope,  V  Z.,  Brit.  Journ.  Surg.,  1916,  iv,  107. 


300     DISORDERS   ASSOCIATED  WITH   THE   PITUITARY 

condition  present,  as  determined  by  all  the  scientific  methods 
of  investigation  at  our  disposal.  At  present,  sufficient  attention 
does  not  appear  always  to  be  directed  to  this  all-important 
question  of  the  nature,  situation  and  exact  direction  and  extent 
of  the  lesion  which  gives  rise  to  the  symptom  or  symptoms  for 
which  relief  is  sought.  Enough  has  been  said  in  connexion  with 
the  various  operations  to  indicate  the  type  of  case  for  which  the 
better  methods  arc  suitable. 


PART    IV 

THE    THERAPEUTICAL    USES 

OF 

PITUITARY    EXTRACTS 


PART   IV 

THE    THERAPEUTICAL   USES   OF   PITUITARY 

EXTRACTS 

§  i.   GENERAL    CONSIDERATIONS 

The  extracts  made  from  the  pituitary  have  as  many  names 
as  there  are  trade-firms  manufacturing  these  products.  I  shall 
endeavour  as  far  as  possible  to  avoid  the  use  of  such  terms  for 
obvious  reasons. 

These  extracts  have  been  prepared  from  the  whole  gland, 
from  the  pars  anterior  alone,  and  from  the  pars  posterior  ;  con- 
sequently they  may  be  described  as  extract  of  the  whole  gland, 
of  the  pars  anterior,  and  of  the  pars  posterior.  If  the  most 
suitable  and  convenient  nomenclature  for  these  extracts  could 
be  generally  adopted  they  would  probably  be  described  as  pitui- 
tarin,  hypophysin,  and  infundibulin  respectively  ;  but  as  already 
stated  these  and  other  terms  have  been  so  incorrectly  and 
indiscriminately  used  by  competing  firms  as  to  make  this 
impossible1.       The    term    '  infundibulin  ',    however,    which    was 

1  In  their  propaganda  for  placing  these  products  before  the  medical  profession 
some  firms  have  issued  pamphlets  which  purport  to  give  a  resume  of  the  original 
work  on  which  the  various  claims  put  forward  in  respect  of  the  extracts  are  based. 
These  accounts  are  often  intentionally  inaccurate,  in  that  the  literature  quoted 
refers  only  to  work  done  itnth  the  preparations  made  by  the  firms  concerned.  In  this 
way  credit  has  been  wrongly  given  to,  and  assumed  by,  continental  clinicians  for 
what  was  discovered  and  described  in  this  country  at  least  a  year  before  the  first 
continental  paper  appeared  ;  and,  unfortunately,  some  medical  writers  appear 
to  obtain  their  historical  information  from  these  pamphlets,  rather  than  from  the 
scientific  literature  on  the  subject.  That  section  of  the  medical  profession,  too, 
which  relies  on  trade-announcements  for  guidance  in  therapeutical  matters  should 
be  warned  against  accepting  the  extravagant  and  often  dangerous  claims  that  have 
been  made.  It  is  only  fair  to  add  that  there  are,  on  the  other  hand,  firms  that 
publish  accurate  and  reliable  information. 


302     THERAPEUTICAL  USES  OF  PITUITARY  EXTRACTS 

originally  introduced1  for  the   extract  of  the  pars  posterior,  will 
be  used  here. 


METHODS    OF    MANUFACTURE 

I  am  indebted  for  the  following  particulars  concerning  the 
preparation  of  pituitary  extracts  for  the  market  to  Dr.  H.  E. 
Annett  of  the  Runcorn  Research  Laboratories. 

Carefully  selected,  healthy  glands  are  taken,  and,  after  all 
the  extraneous  tissues  have  been  removed,  they  are  treated  for 
the  preparation  of  liquid  extracts  or  of  dried,  powdered  products. 

Dried-gland  preparations  are  obtained  in  the  following  way, 
according  to  the  product  required.  The  pars  anterior  or  the 
pars  posterior — which  are  easily  separated — or  the  whole  pituitary 
gland  is  finely  minced  in  a  sterilized  mincing  apparatus,  and, 
after  the  '  wet  weight  '  has  been  noted,  is  dried  in  vacuo  at  a  low 
temperature,  and  afterwards  ground  to  a  fine  powder.  The  '  dry 
weight  '  is  then  obtained,  and  the  relation  of  this  to  the  '  wet 
weight  '  is  recorded. 

Liquid  extracts. — The  whole  gland,  or  a  portion  of  the  gland, 
such  as  the  pars  posterior  from  which  infundibulin  is  prepared, 
is  extracted  with  saline  solution.  The  albuminous  matter  is 
removed  ;  the  liquid  is  sterilized  by  filtration  through  unglazed 
porcelain,  and  then  is  distributed  by  bacteriological  methods. 
The  final  preparation  is  again  tested  in  regard  to  its  absolute 
freedom  from  microorganisms. 

The  usual  strength  of  the  liquid  extract  in  the  case  of 
infundibulin  is  0-2  gramme  in  1  c.c.  of  solution.  In  the  case 
of  liquid  extracts  of  the  pars  anterior  the  strength  is  generally 
0-5  gramme  in  1  c.c.  of  solution. 

Infundibulin  and  the  extract  of  the  pars  anterior  are  not 
destroyed  by  boiling  ;  consequently  absolute  sterility  can  always 
be  ensured.  In  the  case  of  infundibulin  physiological  tests  are 
invariably  carried  out  in  regard  to  the  effect  on  the  blood- 
pressure  and  uterine  muscle  of  each  batch  that  is  prepared. 
Should  these  tests  be  satisfactory  the  preparation  is  ready  to 
be  placed  on  the  market. 

1  Bell,  W.  Blair,  Brit.  Med.  Journ.,  1909,  ii,  1609. 


METHODS    OF   ADMINISTRATION  303 


METHODS    OF    ADMINISTRATION 

However  valuable  a  drug  may  be  when  administered  by  the 
method  of  election,  it  may  be  comparatively,  or  completely, 
inert  when  introduced  into  the  body  in  another  way  ;  con- 
sequently it  is  always  of  importance  to  know  the  method  of 
administration  that  will  give  the  maximum  effect  for  the  purpose 
required. 

These  differences  are  dependent  to  some  extent  on  the 
chemical  composition — often  unknown — of  the  substance  em- 
ployed. Thus,  suprarenal  medullary  extract  is  destroyed  by 
the  gastric  juices,  but  the  active  principle  of  the  thyroid  gland  is 
absorbed — so  far  as  we  know,  unaltered — from  the  alimentary 
tract.  On  the  other  hand,  both  these  extracts  can  be  success- 
fully injected  into  the  subcutaneous  tissues. 

The  method  of  administration,  however,  will  depend — other 
conditions  being  equal — on  the  result  required ;  if  an  immediate 
and  maximum  effect  be  desired  the  substance  must  be  introduced 
directly  into  the  blood-stream,  or  other  tissues  of  the  body,  that 
it  may  be  rapidly  absorbed.  Heaney1  states  that  in  his  observa- 
tions on  the  normal  human  subject,  subcutaneous  injections  of 
infundibulm  produced  only  a  very  slight  rise  in  the  blood-pressure 
and  very  little  slowing  of  the  pulse-rate.  With  intramuscular 
injections  a  definite  rise  in  blood-pressure  and  some  slowing  of  the 
pulse  was  observed.  With  intravenous  injections  great  alterations 
were  observed  :  in  one  case  the  blood-pressure  rose  within  one 
and  one-half  minutes  from  142  mm.  to  200  mm.  Hg,  and  the 
pulse-rate  fell  from  76  beats  in  a  minute  to  54. 

I  have  observed2  that  relatively  greater  effects  follow  intra- 
muscular injections  in  atonic  conditions  of  the  unstriped  muscle- 
fibres  than  in  normal  circumstances. 

If  the  substance  be  not  destroyed  by  the  digestive  juices 
and  a  slow  metabolic  result  be  required,  then  oral  administra- 
tion is  indicated. 

In  the  case  of  the  pituitary  extracts  administration  is  effected 
intravenously  or  intramuscularly3  when  a  rapidresult  is  necessary. 

1  Heaney,  N.  S.,  Surg.  Gyncecol.  and  Obstet.,  11113.  xvii.  103. 

2  Bell,  W.  Blair,  Brit.  Med.  Journ.,  1909,  ii,  1609. 

3  If  injected  hypodermic-ally  superficial  sloughs  may  result  from  the  intense 
local  vasoconstriction  ;  consequently  infundibulin  must  be  injected  intramuscularly. 


304     THERAPEUTICAL  USES  OF  PITUITARY  EXTRACTS 

and  orally  when  slow  metabolic  influences  are  required.  It  has 
already  been  stated  that  infundibulin  is  not  destroyed  by  pepsin, 
but  many  believe  that  little,  if  any,  of  this  substance  is  absorbed 
from  the  bowel.  I  have,  however,  seen  very  pronounced  eleva- 
tion of  the  blood-pressure  follow  prolonged  oral  administration. 
As  with  thyroid  extracts,  we  would  expect  the  active  principles 
of  the  pars  anterior  to  be  absorbable  from  the  alimentary  tract 
since  this  structure  is  morphologically  derived  therefrom  ;  but 
we  have  but  little  certain  knowledge  on  this  point,  apart  from 
the  somewhat  indefinite  results  which  may  follow. 

Extracts  of  the  pituitary  are  made,  as  we  have  seen,  in  the 
form  of  dried  and  liquid  preparations.  The  dried  extracts  are 
usually  given  by  the  mouth,  and  the  liquid  intravenously  or 
intramuscularly.  There  is,  however,  no  reason  against  the  oral 
administration  of  the  liquid  extracts  ;  indeed,  in  the  form  of  an 
elixir  pituitary  extracts  are  often  prescribed. 

Dosage.  Dried  extracts  of  the  anterior  lobe,  of  the  posterior 
lobe,  and  of  the  whole  gland  may  be  administered  by  the  mouth 
in  large  quantities — as  much  as  one  hundred  grains  have  been 
given  three  times  a  day.  The  dose  should  be  regulated  by  the 
requirements  of  the  case  and  the  effects  produced. 

Infundibulin,  when  injected  intramuscularly,  must  be  given 
with  caution :  the  quantity  administered  may  vary  from  0-25 
to  1-0  c.c.  In  primary  and  secondary  uterine  inertia  the  amount 
of  the  first  injection  should  never  exceed  0*5  c.c.,  for  a  larger 
quantity  may  have  too  violent  an  action  in  a  susceptible 
woman. 


GENERAL   INDICATIONS    FOR   ADMINISTRATION 

The  most  notable  effects  and  benefits  of  pituitary  medication 
are  obtained  in  those  cases  in  which  a  rapid  result  is  desirable. 
In  such  circumstances  the  extract  used  is  that  made  from  the 
pars  posterior,  and  its  action  is  exerted  upon  all  the  unstriped 
muscle-tissues  of  the  body.  These  effects  have  been  described 
and  illustrated  in  the  physiological  section  of  this  work,  so  they 
need  not  be  rediscussed  here. 

Following  physiological  investigations1  infundibulin  was   first 

1  Bell,  W.  Blair,  and  P.  Hick,  Brit,  Med.  Journ,,  1909,  i,  777.     (Received  for 
publication  Sept.  1908.) 


INDICATIONS    AND    CONTRAINDICATIONS  305 

employed,  in  the  treatment  of  shock,  uterine  atony  and  intestina 
paresis  in  1908 x.  Since  that  time  innumerable  papers  on  this 
subject  have  appeared,  and  a  few  further  indications  for  the  use 
of  infundibulin  when  an  immediate  effect  is  required  have  been 
suggested.  As  we  shall  see,  the  therapeutical  uses  of  the  extract 
made  from  the  pars  anterior  are  not  so  well  defined. 

The  indications  for  the  administration  of  pituitary  extracts 
may  be  divided  into  the  following  categories,  according  to 
the  requirements  of  the  case,  although  sometimes  more  than 
one  action  is  indicated,  especially  when  antagonistic  and  metabolic 
effects  are  required. 

A.  For  pressor  effects  on  : 

(1)  the  circulatory  system  ; 

(2)  the  uterus  ; 

(3)  the  alimentary  tract ; 

(4)  the  urinary  system  ; 

(5)  the  spleen. 

B.  For  supplementary  effects. 

C.  For  antagonistic  and  metabolic  effects. 

GENERAL    CONTRAINDICATIONS 

Infundibulin  should  not  be  administered,  except  possiblv  with 
great  caution  and  in  small  doses,  in  the  following  circumstances. 

When  there  have  been  signs  of  respiratory  failure  during  an 
operation  an  injection  of  infundibulin  may  bring  about  a  fatal  issue. 

Owing  to  the  action  of  this  extract  on  the  blood-pressure  it 
is  entirely  contraindicated  in  cases  of  heart-disease  which  is  not 
compensated ;  even  when  there  is  compensation  none  but  the 
smallest  doses  are  admissible.  Likewise,  this  preparation  is  contra- 
indicated  in  any  condition  associated  with  high  arterial  tension. 

Infundibulin  should  not  be  used  after  operations  involving 
intestinal  repairs,  or  anastomoses,  lest  the  suture  lines  be  torn 
asunder  by  violent  peristalsis. 

Infundibulin  is  absolutely  contraindicated  for  the  stimula- 
tion of  labour  when  there  is  disproportion  between  the  foetal 
head  and  the  maternal  pelvic  measurements.  So,  too,  all  forms 
of  foetal  impaction  or  obstructed  labour,  and  many  forms  of 
abnormal  presentations  form  definite  contraindications  to  its  use. 

1  Bell,  W.  Blair,  Brif.  Med.  Joum.,  1909,  ii.  1609. 

20 


§  ii.  EFFECTS    PRODUCED   BY   PITUITARY   EXTRACTS 
PRESSOR    EFFECTS    OF    INFUNDIBULIN 

CIRCULATORY    SYSTEM 

It  is  worthy  of  note  that  after  the  injection  of  a  full  dose  of 
infundibulin  the  patient  becomes  blanched  owing  to  the  contrac- 
tion of  the  superficial  arterioles.  This  phenomenon  may  alarm 
unnecessarily  an  inexperienced  nurse. 

Shock 

Infundibulin  may  be  used  either  as  a  prophylactic  measure 
for  the  prevention  of  shock,  or  as  a  remedial  agent  when  shock 
is  present. 

This  is  not  the  place  to  discuss  the  various  theories  concerning 
the  causation  of  shock1.  All  surgeons  know  that  the  main  factors 
are  trauma  and  loss  of  blood,  alone  or  together,  and  toxaemia  ; 
and  it  is  generally  agreed  that  a  low  blood-pressure  is  present. 
The  evidence  on  these  points  is  quite  unassailable  ;  and  one  has 
only  to  watch  the  effect  on  the  blood-pressure  of  an  anaesthetic, 
combined  with  loss  of  blood  and  trauma  due  to  operative  pro- 
cedures, to  be  convinced  that  the  maintenance  of  a  satisfactory 
blood-pressure  and  fluid-compensation  are  of  the  greatest  import- 
ance in  the  treatment  of  shock.  And  it  will  be  evident  that  if 
there  have  been  a  considerable  loss  of  blood  no  attempt  should 
be  made  to  raise  the  blood-pressure  until  a  corresponding,  or 
greater,  amount  of  fluid  has  been  passed  into  the  blood-stream 
by  transfusion.     It  cannot,  therefore,  be  too  strongly  emphasized 

1  Since  this  section  was  written  a  memorandum  of  the  Medical  Research  Com- 
mittee has  been  published  (Brit.  Med.  Journ.,  1917,  i,  381).  The  views  expressed 
therein  in  regard  to  treatment  coincide  very  closely  with  those  described  here. 


SHOCK   AND    COLLAPSE  307 

that  although  infundibulin  is  most  valuable  in  the  prophylaxis 
of  shock,  and  in  maintaining  the  blood-pressure  after  the  trans- 
fusion of  saline  solution,  this  preparation  must  not  be  regarded  as 
a  specific  remedy  for  the  treatment  of  shock  which  follows  loss  of 
blood,  unless  that  loss  be  made  good  before  the  patient  is  moribund. 

It  is  probable  that  at  the  present  time  no  case  should  die  of 
shock  after  operation.  Continuous  subcutaneous  saline  infusions 
during  protracted  operations,  and  an  injection  of  1  c.c.  of  a  20  per 
cent,  extract  of  the  pars  posterior  before  the  patient  leaves  the 
table,  will  usually  enable  her  to  be  returned  to  bed  in  good  con- 
dition— provided,  of  course,  that  the  ordinary  precautions  in  the 
matter  of  warmth,  and  of  rapidity  and  gentleness  in  operating 
have  been  taken  into  account. 

No  doubt  the  administration  of  infundibulin  alone  after  an 
extensive  operation  is  of  considerable  value,  provided  no  great 
quantity  of  blood  has  been  lost,  nor  too  great  evaporation  have 
occurred  from  the  peritoneum1.  In  the  shock,  also,  that  super- 
venes on  an  accident  in  which  a  limb,  for  instance,  is  badly  crushed 
or  injured  without  the  loss  of  blood,  infundibulin  is  most  valuable 
to  restore  the  vasomotor  tone. 

One  of  the  great  advantages  of  infundibulin  is  the  length  of 
time  its  action  is  maintained.  I  have  observed  the  blood-pressure 
to  be  beneficially  affected  for  as  long  as  eight  hours  after  a  single 
administration.  This  has  important  bearings,  not  only  in  regard 
to  the  advantage  that  accrues  to  the  patient  from  this  persistent 
action,  but  also  in  that  it  is  both  useless  and  inadvisable  to  repeat 
the  administration  of  this  substance  within  too  short  a  period, 
for  if  this  be  done  a  fall  rather  than  a  rise  in  blood-pressure  is 
produced.  My  own  rule  has  been  not  to  repeat  a  dose  for  at  least 
two  hours,  at  the  end  of  which  time  a  further  pressor  effect  may 
be  obtained. 

Collapse 

In  collapse,  due  to  sudden  failure  of  the  heart's  action,  rather 
than  a  general  vasomotor  paresis,  I  have  come  to  regard  infundib- 
ulin as  useful  only  when  employed  in  very  small  doses  (0'25  c.c  ) 
and    given   intravenously    in    saline.     Elliott2  and  others  consider 

1  I  have  for  man}-  years  employed  a  rubber  sheet  instead  of  a  gauze  pack  in 
order  to  avoid   irritation  of  the   peritoneum  and  evaporation  therefrom. 

2  Elliott,  T.  R.,  Practitioner,  1915  (Special  number),  123. 


308    THERAPEUTICAL  USES  OF  PITUITARY  EXTRACTS 

that  suprarenin  is  more  valuable  as  a  cardiac  restorative  in 
these  circumstances.  At  the  same  time  the  fatal  combination 
of  chloroform  and  suprarenin  must  not  be  forgotten. 


Sepsis 

In  sepsis  of  a  serious  character,  such  as  may  occur  with 
appendicitis  or  puerperal  infection,  infundibulin  is  of  the  very 
greatest  value. 

I  have  used  it  for  the  treatment  of  these  conditions  for  some 
years,  and  am  convinced  that  many  lives  have  been  saved  by 
the  administration  of  0*5  c.c.  of  this  preparation  intramuscularly 
twice  daily,  so  long  as  acute  symptoms  are  present.  Infund- 
ibulin has  also  been  used  with  benefit  in  typhoid  fever. 

Sepsis  produces  a  profound  depression  of  the  blood -pressure, 
and  loss  of  tone  of  the  involuntary  musculature  generally.  This 
is  probably  the  result  of  lesions  in  the  suprarenal  medulla,  which 
I  have  found  in  experimentally  produced  infections  in  guinea- 
pigs.  The  administration,  therefore,  of  infundibulin  counter- 
balances any  temporary  failure  in  the  suprarenal  secretion.  It 
has  already  been  mentioned  that  there  is  naturally  increased 
activity  in  the  pituitary — unless  necrosis  occur- — as  the  result  of 
infections. 

Serum-sickness 

In  this  condition,  in  which  a  state  of  shock  may  be  produced, 
the  intramuscular  injection  of  infundibulin  is  of  great  advantage. 

In  addition  to  the  elevation  of  the  general  blood-pressure, 
the  administration  of  infundibular  extract  is  of  considerable  value 
in  preventing  the  development  of  the  urticarial  weals  which  may 
form  so  distressing  a  feature  of  serum-sickness.  This  beneficial 
result  is  probably  due  to  the  constriction  of  the  arterioles  and 
the  prevention  of  dilatation.  That  there  is  little  or  no  exuda- 
tion at  the  site  of  the  lesion,  but  rather  a  condition  of  temporary 
vasodilatation,  is  shown  by  the  rapidity  with  which  a  weal  dis- 
appears from   one  spot  and  appears  elsewhere. 

It  is  possible  that  infundibulin  would  be  useful  in  the  treat- 
ment of  angioneurotic  oedema — a  similar  condition — but  I  am 
not  aware  of  any  observations  on  the  subject. 


MENOPAUSE.     ASTHMA.     ASTHENIA  309 


Menopausal  flushings 

These  are  due  to  sudden  variations  in  the  blood-pressure — 
probably  the  result  of  an  irregular  action  of  the  thyroid.  I  have 
found  that  if  the  blood-pressure  be  maintained  at  a  slightly 
higher  level  than  normal  by  the  administration  of  infundibulin 
this  discomforting  phenomenon  can  be  entirely  suppressed  or 
made  endurable. 

It  is,  however,  advisable  to  combine  the  administration  of 
infundibulin — given  orally — with  calcium  lactate,  and  eventually 
to  withdraw  the  extract  partly  or  entirely  in  favour  of  the  calcium 
salt,  which  is  a  less  drastic  vasomotor  tonic. 

Spasmodic  asthma 

Infundibulin  is  sometimes  of  great  value  in  relieving  the 
distress  of  an  acute  attack  of  asthma. 

There  can  be  no  doubt  that  when  relief  is  obtained  the  result 
is  due  to  the  production  of  vasoconstriction  of  the  pulmonary 
arterioles.  Apparently,  however,  this  beneficial  action  is  somewhat 
uncertain  in  the  case  of  infundibulin.  The  principle  of  treat- 
ment on  which  this  action  is  based  was  first  demonstrated  in  the 
case  of  ergot1,  and  later  by  the  use  of  suprarenin2. 

Asthenia 

In  chronic  asthenic  conditions  associated  with  a  low  blood- 
pressure  the  tonic  effect  of  the  extract  of  the  posterior  lobe  is 
most  beneficial.  In  these  circumstances  it  is  advisable  to  give 
either  the  extract  of  the  whole  gland  in  five-grain  doses  three 
times  a  day,  or  an  extract  of  the  pars  posterior  in  doses  of 
two  grains  twice  a  day. 

A  considerable  amount  of  work  has  been  done  on  this  aspect 
of  the  subject  by  Renon  and  Delillc3,  by  Musser4  and  others. 

1  Bell,  W.  Blair,  Edin.  Med,  Journ.,  189!),  xlviii,  339. 

2  Meulangracht,  E.,  Ugeskr.  f.  Loeger,  Copenhagen,  1913,  Ixxv,  1847. 

3  Renon,  L.,  and  A.  Delille,  Bull.  gen.  d.  Ther.,  1907,  cliii,  178. 

4  Musser,  J.  H.,  Amer.  Journ.  Med.  Scl,  1913,  cxlvi,  208. 


310     THERAPEUTICAL  USES   OF  PITUITARY  EXTRACTS 


UTERUS 

Since  the  discovery  of  the  pressor  action  of  the  extract  of 
the  pituitary,  and  of  the  pars  posterior  in  particular,  it  is  probable 
that  the  extract  has  been  used  in  physiological  laboratories  for 
the  comparative  testing  of  the  pressor  substances.  Thus  we 
find  that  Dale1  illustrated  the  action  of  an  extract  of  the  pars 
posterior  on  the  uterus  in  a  paper  relating  to  the  action  of  ergot ; 
but  he  did  not  suggest  the  possibility  of  its  clinical  application. 

In  1908  we2  studied  experimentally  the  action  of  infundibulin 
on  the  uterus,  and  applied  our  results  to  clinical  practice3. 

Obstetrical  uses 

Among  the  vast  number  of  papers  concerning  the  obstetrical 
uses  of  infundibulin  that  subsequently  appeared  it  will  be  suffic- 
ient to  call  attention  to  those  of  Foges  and  Hof staffer4, 
Frankl-Hochwart  and  Frohlich5,  Hofbauer6,  Schmid7:  Jaeger8, 
Watson9,  and  Madill  and  Allan10. 

The  remarkable  position  that  infundibulin  has  come  to 
occupy  in  obstetrical  practice  has  been  the  subject  of  frequent 
comment.  Watson9,  writing  in  1913  of  the  value  of  pituitary 
extract  in  obstetrics,  introduces  his  subject  with  the  following 
words  :  "It  seldom  happens  that  a  new  drug  or  remedy 
comes  into  universal  use  in  such  a  short  space  of  time  as  has 
been  the  case  with  pituitary  extract  in  obstetrical  practice. 
Since  it  was  first  used  ...  in  1909  it  has  been  employed  in 
practically  every  obstetrical  clinic  throughout  this  continent, 
and  in  Britain  and  Europe." 

This  very  popularity  has  led  to  extravagant  claims  being 
made  in  regard  to  the  virtues  of  this  extract.  More  than  one 
writer  has  stated  that  forceps  are  no  longer  required  in  difficult 

1  Dale,  H.  H.,  Journ.  Physiol,  1906,  xxxiv,  163. 

2  Bell,  W.  Blair,  and  P.  Hick,  Brit.  Med.  Journ.,  1909,  i,  777. 

3  Bell,  W.  Blair,  Brit.  Med.  Journ.,  1909,  ii,  1609. 

4  Foges,  A.,  and  R.  Hofstatter,  Zentralbl.  /.  Gynak.,  1910,  xxxiv,  1500. 

5  Frankl-Hochwart,  L.  v.,  and  A.  Frohlich,  Arch.  /.  exper.  Pathol,  u.  Pharmakol., 
1910,  lxiii,  347. 

6  Hofbauer,  J.,  Zentralbl.  f.  Oynak.,  1911,  xxxv,  137. 

7  Schmid,  H.  H.,  Gynah  Rundschau,  1911,  v,  (Reprint). 

8  Jaeger,  F.,  Munch.  Med,  Woch.,  1912,  lix,  297. 

9  Watson,  B.  P.,  Canad.  Med.  Assoc.  Journ.,  1913,  iii,  739. 

10  Madill,  D.  G.,  and  R.  M.  Allan,  Surg.  Gynaecol,  ami  Obstet.,  1914,  xix,  241. 


OBSTETRICAL    USES  311 

labour.  Such  statements  are  not  only  ridiculous,  but  positively 
dangerous.  Properly  used,  infundibulin  is  analeptic ;  improperly 
employed  it  may  be  catastrophic. 

The  indications  for  the  use  of  infundibulin  in  pregnancy, 
parturition  and  the  puerperium,  are  now  well  defined. 

The  dosage  of  infundibulin  in  parturition  is  a  matter  of  great 
importance.  The  quantity  injected  in  the  first  instance  should 
never  exceed  0*5  c.c.  An  even  smaller  quantity  may  advan- 
tageously be  used  in  these  circumstances. 

Induction  of  labour. — Although  abortion  has  never  been 
produced  by  the  administration  of  infundibulin,  there  is  no  doubt 
that  labour  may  occasionally  be  induced  towards  the  end  of  the 
period  of  gestation  by  repeated  intramuscular  injections. 

Stern1,  Fries2,  Hofbauer3,  Goebel4,  Krakauer5,  Stolper6, 
Hager7,  Herzberg8,  Watson9  and  others,  have  reported  suc- 
cessful results,  and  I  have  myself  on  several  occasions  induced 
premature  labour  by  the  use  of  the  extract  alone.  On  the  other 
hand,  failure  to  induce  labour  has  been  very   common3,  10,  1X. 

Impressed  with  these  facts,  and  noting  the  remarkable  action 
of  this  extract  in  cases  of  primary  uterine  inertia,  I  came  to  the 
conclusion  that  infundibulin  not  only  augments  contractions  in 
the  expulsively  contracting,  or  potentially  contracting,  uterus, 
but  also  sensitizes  the  non-contracting  musculature  which  there- 
after responds  readily  to  mechanical  stimuli,  and  as  a  result  con- 
tracts expulsively  in  a  physiological  manner  after  dilatation  of 
the  cervix  or  mechanical  irritation  with  bougies12. 

Labour  may,  then,  be  induced  in  the  following  manner,  within 
a  few  weeks  of  the  full  term,  or  in  postmaturity  of  the  foetus. 

The  patient  is  confined  to  the  house,  not  necessarily  to  bed, 

1  Stern,  R.,  Berl.  Klin,  Woch.,  1911,  xlviii,  1459. 

2  Fries,  H.,  Munch.  Klin.  Woch.,  1911,  lxviii,  2438. 

3  Hofbauer,  J.,  Munch.  Med.  Woch.,  1912,  lix,  1210. 

4  Goebel  (no  initial  in  original),  Munch.  Med.  Woch,,  1912,  lix,  1669. 

5  Krakauer  (no  initial  in  original),  Bed.  Klin.  Woch.,  1912,  xlix,  2317. 

6  Stolper,  L.,  Zenlralbl.  f.  Gynah,  1913,  xxxvii,  162. 

7  Hager,  W.,  Zenlralbl./.  Gynak.,  1913,  xxxvii,  304. 

8  Herzberg,  S.,  Deut.  Med.  Woch.,  1913,  xxxix,  207. 

9  Watson,  B.  P.,  Canad.  Med.  Assoc.  Journ.,  1913,  iii,  739. 

10  Hirsch,  E.,  Munch.  Med.  Woch.,  1912,  lix,  984. 

11  Xagy,  T.,  Zenlralbl.  f.  Gynah,  1912,  xxxvi,  300  and  826. 

12  Bell,  VV.  Blair,  Proc.  Roy.  Soc.  Med.  (Obslet,  and  Gyncecol.  Sect.),  1915,  viii,  71. 


312     THERAPEUTICAL   USES  OF  PITUITARY  EXTRACTS 

and  1  c.c.  of  infundibulin  (20  per  cent.)  is  injected  intra- 
muscularly at  night  and  in  the  morning  for  three  days.  It  is 
advisable  that  the  patient  should  lie  down  for  an  hour  after 
each  injection.  At  the  end  of  this  period  two  or  more  bougies 
are  inserted  into  the  uterus  in  the  ordinary  way,  immediately 
after  the  last  injection  has  been  given.  If  labour  does  not 
commence  within  twelve  hours  another  intramuscular  injection 
of  infundibulin  is  administered. 

In  a  somewhat  limited  experience  I  have  not  known  the 
induction  of  labour  to  be  delayed  for  so  long  as  twenty-four  hours 
after  the  insertion  of  the  bougies  ;  yet  it  is  well  known  how  un- 
certain is  the  action  of  bougies  alone.  A  larger  experience  may, 
of  course,  somewhat  modify  my  present  opinion  of  the  celerity 
of  this  method  of  induction. 

I  have  said  that  preliminary  treatment  with  infundibulin 
should  be  carried  out  for  three  days  before  the  bougies  are  in- 
serted, but  it  should  be  remembered  that  labour  may  be  induced 
before  this  time,  and  so  render  the  insertion  of  bougies  un- 
necessary. On  the  other  hand,  it  may  be  essential  that  the 
administration  of  infundibulin  be  continued  for  a  longer  pre- 
paratory period  than  three  days.  The  obstetrician  can  decide 
the  necessity,  or  otherwise,  of  the  continuance  of  the  administra- 
tion of  infundibulin  by  observing  the  state  of  the  uterus.  The 
effect  of  infundibulin  on  the  uterus  before  parturition  is  very 
striking  :  the  eventual  sensitization  of  the  musculature  is  such 
that  the  slightest  stimulus,  such  as  gentle  manual  kneading, 
causes  the  uterus  to  spring  to  attention — that  is,  to  contract 
firmly.  This  state  must  be  produced  before  the  bougies  are 
inserted. 

It  has  been  suggested1  that  the  effect  of  infundibulin  on  the 
pregnant  uterus  may  be  used  to  distinguish  labour  pains  from 
other  pains  occurring  in  the  normal  course  of  pregnancy.  But 
it  is  doubtful  if  such  a  test  would  be  reliable  in  view  of  the 
action  of  infundibulin  on  the   intestine. 

Primary  uterine  inertia. — The  precise  cause  of   the  uterine 

contractions  in  labour  is  still  unknown,  although  all  the  evidence 

at  our  disposal  points  to  the  presence  of  some  pressor  substance 

in  the  blood  which  sensitizes  the  uterus  to  such  an  extent  that 

1  Benthin,  W.,  Zeitschr.  f.  Geb.  u.  Gynah,  1912,  lxx,  60. 


OBSTETRICAL   USES  313 

the  foetus  and  placenta  play  the  part  of  foreign  bodies  stimulating 
the  musculature  to  expulsive  contractions.  And  it  is,  no  doubt, 
some  deficiency  in  the  sensitizing  and  pressor  substance  or  sub- 
stances that  is  responsible  for  the  condition  known  as  primary 
uterine  inertia. 

It  is  important  that  primary  uterine  inertia  should  be  recog- 
nized before  labour.  This  is  not  difficult,  owing  to  the  flabby 
state  of  the  uterus  which  is  indifferent  to  stimulation,  to  the 
low  general  blood-pressure,  and  to  the  subnormal  calcium  index 
in  the  blood1.  Such  a  state  should  be  treated  by  the  oral  adminis- 
tration of  calcium  salts  and  the  dried  extract  of  the  posterior 
lobe  (gr.  v  ter  in  die)  or  of  the  whole  gland  (gr.  xx  ter  in  die). 

It  is  an  interesting  fact,  which  will  come  under  our  notice 
again  later,  that  infundibulin  not  only  directly  sensitizes  the 
uterus,  but  also  influences  beneficially  the  retention  of  calcium 
salts  in  the  blood  and  tissues  of  the  body.  I  have  seen  women 
with  bad  obstetrical  histories  in  regard  to  primary  uterine  in- 
ertia, go  through  easy  and  rapid  labours  after  treatment  in  the 
manner  described. 

When  labour  has  commenced  and  the  uterine  contractions 
are  feeble  and  ineffective,  if  there  be  no  contraindications,  such 
as  disproportion  between  the  maternal  and  foetal  measurements, 
malpositions  or  obstructed  labour,  infundibular  extract  (0*5  c.c.) 
should  be  injected  intramuscularly.  As  a  rule,  the  contractions 
are  increased  in  force  and  frequency  within  a  few  minutes,  and 
the  character  of  the  contractions  is  entirely  physiological  and 
rhythmical  (fig.  187). 

Further  injections  may  be  administered  if  necessary  after 
intervals   of  a  few  hours. 

Madill  and  Allan2,  in  their  series  of  cases  at  the  Rotunda 
Hospital  in  Dublin,  administered  infundibulin  for  primary 
uterine  inertia  to  four  primigravidae  and  nine  multiparas.  The 
first  injection  was  given  to  the  former  when  the  os  uteri  was 
one  half  to  three  quarters  dilated  and  after  the  patient  had 
been  in  labour  for  an  average  time  of  twenty  hours.  The  sub- 
sequent duration  of  labour  was  on  an  average  only  two  hours. 
In  the  cases  of  multiparae,  who  had  been  in  labour  for  an  average 
time  of  thirteen  hours,   the  first   injection   was   given    when   the 

1  Bell,  W.  Blair,  Proc.  Roy.  Soc.  Med.  (Obstel.  and  Gynozcol.  Sect.),  1915,  viii,  71. 

2  Madill,  D.  O..  and  R.  M.  Allan,  Surg.  Gyncecol.  and  Obsttt.,  1914,  xix,  241. 


314    THERAPEUTICAL  USES  OF  PITUITARY  EXTRACTS 

os  was  one  quarter  dilated.      The  subsequent  average  period  of 
labour  in  these  cases  was  only  forty  minutes. 

These    authors,  like    Strassmann1    and    most  other  observers, 


Fig.   187. 

Kymograph -tracing  showing  the  increase  in  regular  physiological  uterine 
contractions  during  labour  after  an  intramuscular  injection  of  0-6  c.c,  of 
infundibulin  in  primary  inertia.      (Malinowshy.) 

found  that  the  placenta  is  expelled  in  about  fifteen  minutes — a 
shorter  period  than  is  usual  in  normal  labour. 

Secondary  uterine  inertia. — It  is  probable  that,  other  con- 
ditions being  suitable,  the  use  of  infundibulin  in  secondary  uterine 
inertia — a  very  common  condition — far  exceeds  all  other  applica- 
tions of  the  effect  of  this  preparation  on  the  uterus. 


Fig.  188. 
Kymograph-tracing  showing  the   resumption  of    regular  physiological  uterine 
contractions  after  an  intramuscular  injection  of  1'2  c.c.  of  infundibulin  in  secondary 
inertia.      (Malinowshy.) 

In  these  circumstances  the  head  is  usually  in  the  pelvis,  and 
the  labour  '  pains  '  have  either  ceased  or  have  diminished  in 
frequency  and  force.  Following  the  intramuscular  injection  of 
0-5  c.c.  of  infundibular  extract  there  is,  almost  immediately,  re- 
establishment  of  rhythmical  and  forcible  uterine  contractions 
(fig.  188).  This  is  illustrated  by  Madill  and  Allan2,  who  have 
published  a  series  of  charts  in  their  paper  to  show  the  duration 

1  Strassmann,  P.,  Zentralbl.  f.  Gynah,  1912,  xxxvi,  438. 

2  Madill,  D.  G.,  and  R.  M.  Allan,  Surg.  Gynaecol,  and  Obstet.,  1914,  xix.  241. 


OBSTETRICAL   USES  315 

and  force  of  the  '  pains  '  (fig.  189).  In  these  charts  the  effect 
of  infnndibulin  on  the  fcetal  heart  is  recorded.  Similar  charts 
had  previously  been  published  by  Jaeger1. 

The  children  born  after  the  use  of  infundibular  extract  are 
sometimes  cyanosed  and  have  a  slow  heart-action  1>  2>  3>  4> 5. 

It  is  possible  that  the  condition  of  the  fcetal  heart  is  caused 
by  the  infundibulin  circulating  in  the  maternal  blood,  and  that 
the  cyanosis  is  due  to  the  rapidity  of  recurrence  and  to  the  force 
of  the  uterine  contractions. 

Anaesthetics  have  but  little  effect  in  diminishing  the  con- 
tractions produced  by  infundibulin5  ;  nor  do  opium  derivatives 
interfere  with  its  action — Schmid6,  indeed,  advises  that  pant- 
opon be  used  in  conjunction  with  infundibulin  as  a  routine  pro- 
cedure. I  have  found  that  omnopon,  or  scopolamin  and  morphin 
('  twilight-sleep  '),  may  very  advantageously  be  combined  with 
infundibulin,  in  order  to  shorten  the  period  of  labour. 

Placenta  prasvia.  —  In  this  condition  infundibulin  appears 
to  have  been  widely  used,  and  many  observers  5>  6> 7-  8>  9>  10>  u»  who 
have  employed  it — usually  in  conjunction  with  rupture  of  the 
membranes,  hydrostatic  bags,  vaginal  packing,  or  with  turning — 
are  convinced  of  its  value  in  safely  effecting  delivery,  provided 
the  other  conditions  are  favourable  for  its  administration. 

It  will  be  obvious  that  the  best  effect  of  infundibular  extract 
will  be  obtained  when  the  placenta  prasvia  is  not  central  ;  never- 
theless, good  results  have  been  obtained  even  when  the  placenta 
has  been  more  or  less  centrally  situated  over  the  os  uteri. 

Accidental  haemorrhage. — In  the  absence  of  definite  contra- 
indications, and  after  rupture  of  the  membranes,  an  intramuscular 

1  Jaeger,  P.,  Munch.  Med.  Woch.,  1912,  lix,  297. 

2  Hofbauer,  J.,  Zentralbl.  f.  Gynak.,  1911,  xxxv,  137. 

3  Fischer,  O.,  Zentralbl.  f.  Gynak.,  1912,  xxxvi,  15. 

4  Lieven,  ¥.,  Zentralbl.  f.  Gynak.,  1913,  xxxvii,  337. 

5  Madill,  1).  G.,  and  R.  M.  Allan,  Surg.  Gyncecol.  and  Obstet.,  1914,  xix,  241. 

6  Sclmiid,  H.  H.,  Gynak.  Rundschau,  1911,  v,  (Reprint). 

7  Bell,  W.  Blair,  Brit.  Med.  Joum.,  1909,  ii,  1609. 

8  Hofbauer,  J.,  Munch.  Med.  Woch.,  1912,  lix,  1210. 

9  Watson,  B.  P.,  Canad.  Med.  Assoc.  Joum.,  1913,  iii,  739. 

10  Studeny,  A.,  Wien.  Klin.  Woch.,  1911,  xxiv,  1766. 

11  Gall,  M.  E.,  Zentralbl.  f.  Gynak.,  1913,  xxxvii,  77. 


316     THERAPEUTICAL  USES  OF  PITUITARY  EXTRACTS 


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OBSTETRICAL   USES  317 

injection  of  infundibulin  may  form  a  valuable  adjunct  to  other 
treatment,  even  if  it  be  not  entirely  effectual  in  itself. 

Postpartum  haemorrhage. — Infundibulin,  owing  to  its  rapid 
action  on  the  uterus  after  intramuscular  injection,  is  very 
valuable  in  postpartum  haemorrhage  lj  2>  3.  At  the  same  time, 
since  the  contractions  produced  by  this  preparation  in  the  uterus 
are  rhythmical  in  character,  its  action  is  probably  not  always 
so  lastingly  effective  as  the  preparations  of  ergot  which  produce 
tetanic  spasm  of  the  uterine  musculature.  But  it  has  been  found 
that  the  action  of  ergot  is  increased  by  simultaneous  or  previous 
sensitization  of  the  uterus  with  infundibulin  ;  consequently  it 
is  advisable  to  use  the  two  drugs  in  combination  for  the  treat- 
ment of  haemorrhage  occurring  post  part  urn . 

Caesarean  section. — Infundibulin  has  been  extensively  used 
with  most  beneficial  results1'2,3'4'5.  The  injection  may  be 
made  in  the  maternal  muscles  during  the  operation,  or  directly 
into  the  uterine  muscle  after  the  uterus  has  been  emptied.  In 
my  experience  the  former  method  is  the  better,  for  if  the  extract 
be  injected  directly  into  the  uterus,  that  organ  may  become  so 
tightly  contracted  that  it  is  difficult  to  suture  the  wound  in 
the  muscle- wall. 

Acute  subinvolution. — It  has  been  found  that  when  there  is 
no  such  cause  for  subinvolution  as  fibromyomata  uteri  or  other 
gross  pathological  lesion,  the  condition  can  be  effectually  treated 
by  the  daily  administration  of  infundibulin.  It  is,  however,  in 
these  cases  advisable  also  to  prescribe  calcium  salts  during  the 
treatment  with  pituitary  extract  and  after  this  extract  has  been 
discontinued. 

Abortion. — Infundibulin  is  ineffectual  in  causing  the  expulsion 
of  the  ovum  and  placenta  in  the  first  half  of  the  period  of  gesta- 
tion. Indeed,  the  uterus  is  generally  found  to  contract  down 
on   and  grasp  the   embryo  and   placenta,   and  the  cervix   to  be 

1  Bell,  W.  Blair,  Brit.  Med.  Journ,,  1909,  ii,  1609. 

2  Foges,  A.,  and  R.  Hofstatter,  Zentralbl.  /.  Oynak.,  1910,  xxxiv,  1500. 

3  Schmid,  H.  H.,  Gynalc.  Rundschau,  1911,  v,  (Reprint). 

4  Hofbauer,  J.,  Zentralbl.  f.  Oynak.,  1911,  xxxv,  137. 

5  Herzberg,  S.,  Deut.  Med.  Woch.,  1913,  xxxix,  207. 


318    THERAPEUTICAL  USES   OF  PITUITARY  EXTRACTS 

tightly  closed1, 2.  If,  however,  the  uterus  have  been  emptied, 
the  administration  of  infundibulin  is  very  valuable,  when  injected 
intramuscularly  daily  for  a  few  days  to  induce  proper  involution. 

Bad  effects  stated  to  have  followed  the  use  of  infundib- 
ulin in  obstetrical  practice 
A  few  cases  have  been  recorded  in  which  the  administration 
of  infundibulin   is   said  to   have  produced  rigidity  of  the  cervix 
during  labour  3-  4-  5.      This  must  be  a  most  unusual  circumstance, 
and  the  accounts  of  these  cases  are  somewhat  unsatisfactory. 

Hour-glass  contraction6  of  the  uterus  after  the  birth  of  the 
child,  and  postpartum  haemorrhage7  following  injections  of  in- 
fundibulin have  been  recorded.  There  can  be  no  doubt  that 
both    these    occurrences    would   be   likely   if    the    placenta   were 


Fig.   190. 

Kymograph-tracing  showing  tetanic  uterine  contractions  of  short  duration, 
followed  by  powerful  rhythmical  contractions  after  an  intramuscular  injection  of 
infundibulin  in  secondary  uterine  inertia.     {Malinoivsky.) 

unduly  retained.  To  avoid  such  accidents,  when  infundibulin 
has  been  given  during  labour,  it  is  advisable  to  express  the 
placenta  at  the  end  of  twenty  minutes  after  the  birth  of  the 
child,  if  it  have  not  already  been  expelled. 

Rupture  of  the  uterus,  which  is  quite  avoidable  and  is  a  serious 
reflexion  on  the  accoucheur,  has  followed  the  administration  of 
infundibulin  when  there  has  been  obstruction  to  delivery.  A  certain 
number  of  these  disasters  is  on  record,  and  several  have  been 
privately  communicated  to  me.  I  myself  have  never  seen  such 
a  mishap. 

1  Hamm,  A.,  Munch.  Med.  Woch.,  1912,  lix,  77. 

2  Watson,  B.  P.,  Canad.  Med,  Assoc.  Journ,,  1913,  iii,  739. 

3  Mackenrodt  (no  initial  in  original),  Zentralbl.  f.  Gynak.,  1911,  xxxv.  679. 

4  Heil,  K.,  Zentralbl.  f.  Gynak.,  1912,  xxxvd,  1398. 

5  Rieck  (no  initial  in  original),  Munch.  Med.  Woch.,  1912,  lix,  816. 

6  Glass,  R.  L.,  Brit.  Med.  Journ.,  1914,  ii,  72. 

7  Levinson,  W.  E.,  Brit.  Med.  Journ.,  1914,  iis  1046. 


CONTRAINDICATIONS    TO   OBSTETRICAL    USES     319 

Malinowsky1  states  that  he  has  seen  tetanic  spasms  (fig.  190) 
in  the  uterus  lasting  for  one  quarter  of  an  hour  when  infundibulin 
has  been  injected  before  the  dilatation  of  a  rigid  cervix  ;  but  he 
states  that  the  spasms  disappeared  as  labour  advanced. 

I  have  already  referred  to  the  slight  bad  effects  that  have 
occasionally  been  observed  in  regard  to  the  child. 


Contraindications  to  the  use  of  infundibulin  in  obstetrical 

practice 

If  the  mother  be  the  subject  of  disease  of  the  heart  or 
kidneys,  especially  with  arteriosclerosis,  this  preparation  is 
dangerous  and  may  be  fatal. 

Madill  and  Allan2  record  a  case  of  heart-disease  in  which  in- 
fundibulin was  administered  for  uterine  inertia.  As  a  result  of 
this  treatment  the  patient  collapsed,  and  was  with  difficulty 
resuscitated  with  stimulants. 

Hauch  and  Meyer3,  and  Brammer4,  also,  advise  against  the 
use  of  infundibulin  if  the  mother  suffer  with  cardiac  or  renal 
disease  ;  and  the  former  also  call  special  attention  to  the  fact 
that  this  extract  should  not  be  used  in  the  presence  of  eclamptic 
manifestations  with  a  high  blood-pressure. 

It  is  only  right,  however,  to  state  that  certain  writers5,  6 
state  that  kidney-disease  is  not  a  contraindication  to  the  use  of 
infundibulin.  As  a  matter  of  fact,  the  state  of  the  blood-pressure 
should  afford  a  clue  as  to  the  safety  or  otherwise  of  the  ad- 
ministration of  the  extract  in  these  circumstances. 

Owing  to  the  high  blood-tension  usually  found  in  eclampsia 
I  have  never  felt  justified  in  using  infundibulin  to  induce  or 
terminate  labour  in  these  circumstances.  Krakauer7  and  others 
have,  however,  employed  the  extract  for  these  purposes. 

With  regard  to  the  local  conditions — fcetal  and  maternal- 
there  are  many  important  contraindications  to  the  use  of  infundib- 
ulin. 

1  Malinowsky,  M.,  Zentralbl.  f.  Gynak.,  1912,  xxxvi,  1425. 

2  Madill,  D.  G.,  and  R.  M.  Allan,  Surg.  Gynaecol,  and  Obstet.,  1914,  xix,  241. 

3  Hauch,  E.,  and  L.  Meyer,  Hopitalstidende,  Copenhagen,  1912,  lv,  389. 

4  Brammer,  M.,  Hopitalstidende,  Copenhagen,  1912,  lv,  389. 

5  Stern,  R.,  Zentralbl.  f.  Gynak.,  1911,  xxxv,  1113. 

6  Gussew,  W.,  Zentralbl.  J.  Gynak.,  1912,  xxxvi,  1755. 

7  Krakauer  (no  initial  in  original),  licrl.  Klin.  Woch.,  1912,  xlix,  2317. 


320    THERAPEUTICAL   USES   OF  PITUITARY  EXTRACTS 

In  malpositions  of  the  foetus,  such  as  the  oblique  and  the 
persistent  mentoposterior  positions,  which  render  it  impossible 
for  the  child  to  be  born  unless  there  be  an  alteration  of  the 
attitude,  the  uterus  may  be  ruptured  by  the  violent  contractions 
induced  by  this  oxytocic. 

So,  too,  when  there  is  undue  disproportion  between  the  fcetal 
head  and  the  maternal  passages — a  state  that  exists  to  some 
extent  in  all  normal  primigravidce — or  there  is  obstructed  labour 
from  any  cause  whatsoever,  infundibulin  should  not  be  given  to 
augment  the  force  of  the  uterine  contractions  lest  rupture  of 
the  uterus  occur;  and  in  elderly  primigravidae  where  the  rigid 
parts  may  be  lacerated  the  drug  must  be  used  with  caution. 

Although  infundibulin  has  been  employed  successfully  in 
minor  degrees  of  obstruction  and  in  some  malpositions,  such 
temerity  on  the  part  of  the  accoucheur  does  not  detract  from  the 
fact  that  its  use  in  such  circumstances  is  highly  dangerous. 

From  these  remarks  it  will  be  evident  that  in  experienced 
hands,  when  the  indications  and  contraindications  are  duly  con- 
sidered, no  bad  effects  either  to  the  mother  or  child  are  likely  to 
follow. 

Gynaecological  uses 

In  menorrhagia  due  to  increased  or  irregular  activity  in  the 
thyroid  and  ovaries — such  as  is  seen  at  puberty  and  the  meno- 
pause— intramuscular  injections  of  infundibulin  are  invaluable. 
Likewise,  in  those  cases  in  which  there  is  menorrhagia  with 
intrauterine  clotting  of  the  menstrual  blood  as  the  result  of 
decreased  muscular  tone  in  the  uterus  and  involuntary  muscular 
system  generally,  infundibulin  may  bring  about  a  rapid  im- 
provement. 

In  these  cases  it  is  advisable  to  administer  the  infundibular 
extract  during  menstruation  only  and  to  prescribe  calcium 
salts1  during  the  menstrual  intervals. 

Apart  from  excessive  menstruation  infundibulin  will,  tempor- 
arily, at  any  rate,  control  bleeding — due  to  almost  any  cause — 
from  the  corpus  uteri2  owing  to  its  action  on  the  muscle-fibres. 

1  Mist,  calcii  lactatis  recentis  (C  &  A)  :   ^i  om.  nocte. 

2  Bab,  H.,  Munch.  Med,  Woch,,  1911,  lviii,  1554. 


ALIMENTARY   TRACT.      URINARY   SYSTEM        321 

ALIMENTARY    TRACT 

Infundibulin  may  be  used  to  prevent  and  to  relieve  acute 
paralytic  distension  of  the  stomach  and  intestine  which  is  sometimes 
seen  after  abdominal  operations.  We  first  called  attention  to 
this  in  1909 12.  Since  that  time  many  observers  have  recorded 
their  experiences  3>  4> 5 ;  and  the  preparation  is  now  very  generally 
used  in  preference  to  eserine  and  the  other  drugs  previously 
employed  to  stimulate  peristalsis. 

The  contraindications  already  mentioned,  namely,  cardiac 
disease,  renal  disease  associated  with  a  high  blood-pressure,  and 
intestinal  suture,  prohibit  the  use  of  infundibulin  in  the  circum- 
stances under  consideration  ;  and  this  is  more  especially  the  case 
since  to  secure  pronounced  peristalsis  large  doses  are  necessary — 
that  is  to  say,  1  to  2  c.c.  of  the  extract.  In  intestinal  paresis, 
or  distension,  following  abdominal  operations,  I  have  found, 
however,  that  1  c.c.  of  infundibulin  is  always  enough  if  a  tur- 
pentine enema  be  given  ten  minutes  after  an  intramuscular 
injection  of  the  extract. 

It  is  probable,  too,  that  the  best  results  are  obtained  with 
acute  gastric  distension  if  the  stomach  be  washed  out  ten  minutes 
after  an  intramuscular  injection  of  infundibulin. 

In  chronic  constipation  the  continued  oral  administration  of 
an  extract  of  the  whole  gland  or  of  infundibulin  has  given  good 
results  in  many  cases  in  which  the  constipation  has  been  due 
to  loss  of  tone  in  the  intestinal  musculature6. 

URINARY    SYSTEM 

Kidneys. — As  we  have  seen,  Magnus  and  Schafer7  claim  that 
the  extract  of  the  pars  nervosa  has  a  definite  diuretic  effect,  and 
there  is  no  doubt  that  this  preparation  has  been  extensively  used 
for  producing  diuresis.  Hofstatter8  states  that  postoperative 
anuria  is  invariably  relieved  by  injections  of  infundibulin. 

1  Bell,  W.  Blair,  and  P.  Hick,  Brit.  Med.  Journ.,  1909,  i,  777. 

2  Bell,  W.  Blair,  Brit.  Med.  Journ.,  1909,  ii,  1609. 

3  Bidwell,  L.,  Clin.  Journ.  Lond.,  1911,  xxxviii,  351. 

4  Houssay,  B.  A.,  and  J.  Beruti,  Presse  Medicale,  1913,  xxi,  613. 

5  Moyniban,  B.,  Abdominal  Operations,  1914,  i,  63. 

6  Musser,  J.  H.,  Amer.  Journ.  Med.  Sci.,  1913,  cxlvi,  208. 

7  Magnus,  R.,  and  E.  A.  Schafer,  Journ.  Physiol.,  1901,  xxvi,  Ix. 

8  Hofstatter,  R.,  Wien.  Klin.  Woch.:  1911,  xxiv,  1702. 

21 


322  THERAPEUTICAL   USES    OF   PITUITARY   EXTRACTS 

In  my  own  experience  I  have  not  often  noted  clinically  any 
very  definite  diuresis  in  patients  who  have  had  injections  of 
infundibulin  regularly  twice  a  day  for  some  days.  Nevertheless, 
in  the  prevention  and  treatment  of  shock,  in  which  state  the 
secretion  of  the  kidneys  is  diminished,  infundibulin  may  act 
indirectly ;   and  this  applies  especially  to  postoperative  anuria. 

Bladder. — Frankl-Hochwart  and  Frohlich1  have  shown  that 
injections  of  infundibulin  stimulate  the  musculature  of  the 
bladder,  which  subsequently  reacts  more  energetically  to  stimul- 
ation of  the  hypogastric  nerves.  As  a  result  of  their  experi- 
ments these  investigators  have  recommended  the  clinical  use  of 
the  extract  in  paresis  of  the  bladder. 

In  my  experience  the  action  of  even  large  doses  of  infund- 
ibulin on  the  bladder  is  somewhat  uncertain  ;  and  in  postoperat- 
ive paresis  I  have  never  seen  the  bladder  emptied  unless  the 
injection  were  given  when  the  bladder  was  fully  distended,  and 
even  in  these  circumstances  the  extract  often  fails  to  produce 
the  desired  effect. 

I  have,  therefore,  adopted  the  following  procedure,  which 
sometimes  succeeds.  An  intramuscular  injection  of  infundibulin 
is  given  when  the  bladder  is  distended.  If  no  result  is  produced, 
a  catheter  is  passed  and  a  few  ounces  are  allowed  to  flow  through 
it  ;  the  catheter  is  then  withdrawn,  and  after  this  the  patient 
may  continue  to  pass  urine  normally. 


MAMMARY   GLANDS 

Infundibulin,  when  intravenously  injected,  produces  a  rapid 
flow  of  milk  from  the  incised  lactating  breast,  as  already  demons- 
trated; and  there  has  been  much  discussion  as  to  whether  this 
is  an  expulsive  or  a  true  galactogogue  effect. 

The  observations  of  Heaney2  and  others  on  the  human  sub- 
ject leave  no  room  for  doubt  that  any  increased  supply  of  milk 
obtained  is  temporary,  and  is  usually  followed  by  a  decrease ; 
consequently    it    is    certain    that    infundibulin    is   of    little    use 

1  Frankl-Hochwart,  L.  von,  and  A.  Frohlicb,  Arch.  f.  Exper.  Pathol,  u.  Phar- 
mahol,  1910,  lxiii,  347. 

2  Heaney,  N.  S.,  Surg.  Gyn.  and  Obstet.,  1913,  x-sii,  103. 


MAMMARY   GLANDS.      SPLEEN  323 

therapeutically  as  a  galactogogue  when  the  secretion  of  milk  is 
deficient. 

The  employment  of  infundibulin  in  threatened  mammary 
abscess  has  been  suggested,  but  it  is  difficult  to  understand  how 
an  abscess  could  be  aborted  by  this  means. 

SPLEEN 

I  am  not  aware  of  any  cases  recorded  in  the  literature  in  which 
infundibulin  has  been  used  to  produce  contractions  in  the  mus- 
cular tissue  of  the  spleen. 

My  colleague  R.  J.  M.  Buchanan;  however,  has  treated 
successfully  a  serious  case  of  splenomegaly  by  the  oral  adminis- 
tration of  an  extract  of  the  whole  gland. 


SUBSTITUTIONAL    AND    SUPPLEMENTARY    EFFECTS    OF 
PITUITARY  EXTRACTS 

It  is  probable  that  true  substitutional  effects  are  never  observed 
in  the  human  subject ;  that  is  to  say,  total  destruction  or  removal 
of  the  gland  is  not  compatible  with  life,  even  though  substitu- 
tion-therapy be  practised.  We  are,  therefore,  only  concerned 
clinically  with  the  supplementary  effects  of  pituitary  extracts. 

We  have  seen  that  insufficiency  of  the  pituitary  may  produce 
a  very  obvious  train  of  symptoms  giving  rise  to  the  syndrome 
dystrophia  adiposogenitalis  ;  yet  there  is  little  doubt  that  minor 
degrees  of  insufficiency  of  a  temporary  or  permanent  character 
are  by  no  means  uncommon,  just  as  are  the  minor  and  less  easily 
recognized  insufficiencies  of  the  thyroid. 

It  will  be  remembered,  also,  that  dishing1  has  found  that  the 
subnormal  temperature  associated  with  the  high  degrees  of 
pituitary  insufficiency  can  be  elevated  by  injections  of  an  extract 
of  the  pars  anterior,  while  the  low  blood-pressure  is  raised  and 
the  sugar-tolerance  lessened  by  the  administration  of  infundib- 
ulin  ;  consequently  in  such  cases  an  extract  of  the  whole  gland 
is  indicated. 

The  results  of  this  method  of  treatment  are  not  very  good. 
Cushing1  after  a  large  experience  found  that  the  hypodermic 
administration  of  an  extract  of  the  whole  gland  occasionally  gave 
good  temporary  results.  In  one  case,  the  patient  became  active 
mentally  and  physically,  so  the  pituitary  of  a  newly  born  infant, 
which  died  during  birth,  was  grafted  in  the  subcortical  tissues 
of  the  temporal  lobe  of  the  patient  with  complete  operative  and 
therapeutical  success.  Nevertheless,  it  is  difficult  to  estimate 
how  far  this  excellent  result  was  due  to  the  effect  of  the  grafted 
gland,  for  an  hypophysial  cyst  had  been  evacuated  a  few  weeks 
previously,  although  without  any  apparent  benefit. 

1  Cushing,  H.,  The.  Pituitary  Body  and  its  Disorders,  1912. 


SUBSTITUTION   AND    SUPPLEMENTARY   EFFECTS    325 

In  a  case  which  came  under  my  own  notice  in  the  year  1910, 
a  man  almost  completely  blind,  and  suffering  from  adiposity  and 
genital  atrophy  with  impotence,  was  treated  with  hypodermic 
injections  of  an  extract  of  the  pars  anterior  for  a  long  time. 
Eventually  he  recovered  his  potency  and  impregnated  his  wife 
who  gave  birth  subsequently  to  a  full-term  child. 

From  the  evidence  at  our  disposal  it  appears  that  supplement- 
ary medication  should  be  combined  with  surgical  treatment  of 
the  pituitary  lesion;  and,  if  permanent  benefit  is  to  accrue,  that 
implantation  may  offer  the  most  convenient  method  of  meeting 
the  deficiency  of  pituitary  secretion. 

In  the  minor  degrees  of  insufficiency  the  results  obtained 
have  been  fairly  good.  Hofst after1  claims  to  have  had  pro- 
nounced success  in  the  alleviation  of  amenorrhcea  associated 
with  adiposity ;  but  in  some  cases  thyroid  extract  was  also  given. 
Hoist  atter's  method  of  treatment  was  by  hypodermic  medication, 
and  it  was  found  that  coincidental  oral  administration  was  of 
advantage.  In  only  about  a  third  of  the  cases  could  men- 
struation be  preserved  by  frequent  administration  of  the  ex- 
tract. Fromme2  has  obtained  similar  results.  Williams3,  also, 
has  reported  an  interesting  case  of  amenorrhcea  which  was 
successfully  treated  with  pituitary  extract.  If,  in  this  case,  the 
drug  was  discontinued  amenorrhcea  was  again  in  evidence. 

In  my  own  experience,  chiefly  of  oral  administration,  the 
results  have  not  been  striking,  although  in  a  few  patients  scanty 
and  infrequent  menstruation  has  been  induced.  Most  of  the 
patients  have  complained  bitterly  of  the  severity  of  the  headaches 
with  which  they  suffered  while  taking  the  extract  of  the  pars 
anterior. 

It  seems  certain  that,  unless  the  arrest  of  menstruation  is 
subject  to  treatment  at  an  early  period,  genital  atrophy  may 
supervene,  and  render  all  prospect  of  beneficial  treatment 
hopeless. 

In  no  case  have  I  observed  any  decrease  in  the  adiposity  of 
the  subject  after  prolonged  oral  treatment  with  an  extract  of  the 
whole  gland,  or  with  infundibulin,  nor  have  I  seen  a  permanent 
change  in  the  carbohydrate-tolerance  in  these  eireumstanccs.     It 

1  Hofstatter,  R.,  Zenfralbl.  f.  Gynak.,  1912,  xxxvi,  1536. 

2  Fromme,  F.,  Zenfralbl.  f.  Gynak.,  1912,  xxxvi,  1366. 

:i  Williams,  L.,  Proc.  Roy.  Soc.  Med.  (Discussion),  1914,  vii,  37. 


326  THERAPEUTICAL   USES    OF   PITUITARY   EXTRACTS 

appears  probable,  therefore,  that  oral  administration  is  of  little 
value  in  supplementing  diminished  pituitary  secretion. 

Before  we  leave  the  consideration  of  the  supplementary  effects 
of  pituitary  extracts  mention  must  be  made  of  the  fact  that  since 
physiologically  the  pars  anterior  is  supplementary  to  the  thyroid 
and  ovaries — if  we  can  so  interpret  the  hyperplasia  that  occurs 
in  this  part  of  the  pituitary  as  the  result  of  the  removal  of  these 
glands — the  administration  of  the  extract  of  the  pars  anterior 
has  been  suggested  in  primary  hypoplasia  of  the  ovaries  and 
possibly  of  the  thyroid.  But  such  treatment  is  not  indicated,  for 
we  know  that  in  hypoplasia  of  the  thyroid  an  extract  of  this 
organ  itself  effects  a  cure  ;  and  that  in  ovarian  hypoplasia  the 
administration  of  ovarian  extract,  which  of  itself  is  more  or  less 
inert,  together  with  thyroid  extract,  may  be  beneficial1. 

Francesco2,  Barker  and  Hodge3,  and  others  consider  that 
diabetes  insipidus  is  due  to  insufficiency  of  the  pars  posterior  of 
the  pituitary,  and  find  that  injections  of  infundibulin  arrest 
all  the  symptoms  of  this  disease,  including  polyuria4.  This 
somewhat  paradoxical  effect  still  awaits  explanation. 

1  Bell,  W.  Blair,  The  Sex  Complex,  1916  ;  The  Disorders  of  Function  :  The  Neu 
System  of  Gynaecology,  1917. 

2  Francesco,  P.,  Caz.  d.  Osp.  e.  d.  Clin.  Milan,  1913,  xxxiv,  1127. 

3  Barker,  L.  F.,  and  M.  Hodge,  Bull.  Johns  Hopk.  Hosp.,  1917,  xxxiii,  355. 

4  Compare  with  pp.  109  and  177. 


ANTAGONISTIC    AND    METABOLIC    EFFECTS    OF 
PITUITARY    EXTRACTS 

In  the  correlation  of  effects  produced  by  the  hormonopoietic 
organs  we  find  that  antagonistic  and  metabolic  as  well  as  supple- 
mentary actions  are  concerned  ;  so  it  is  possible  to  utilize  extracts 
of  the  pituitary  to  combat  hyperplasia  in  some  and  hypoplasia 
in  other  organs,  and  to  counteract  abnormal  metabolic  states 
that  have  been  produced  by  these  conditions.  Nevertheless, 
our  knowledge  on  these  matters  is  still  most  elementary,  and  the 
extracts  of  the  pituitary  are  used  almost  empirically  for  the 
purposes  indicated. 

It  is,  of  course,  impossible  to  separate  and  to  distinguish  the 
direct  action  of  an  organ  of  internal  secretion  upon  the  meta- 
bolism from  the  effects  of  its  action  on  another  member 
of  the  hormonopoietic  system  and  the  resulting  total  effect  on 
the  metabolism.  The  fact  remains,  however,  that,  should  the 
antagonism  of  the  remedial  agent  succeed,  the  effect  is  seen  not 
only  in  the  metabolism  but  in  the  lessened  activity  of  the  organ 
of  internal  secretion  whose  excessive  activity  has  been  restrained. 

Hyperthyroidism. — The  extract  of  the  posterior  lobe  may 
be  used  in  the  treatment  of  hyperthyroidism.  We  know  that 
thyroid  secretion  lowers  the  blood-pressure  and  leads  to  the  rapid 
excretion  of  lime  salts.  Infundibulin  counteracts  both  these 
effects,  and,  like  suprarenin,  causes  a  rise  in  the  blood-pressure 
and  the  storage  of  lime  salts.  At  the  same  time,  it  often  effects  a 
diminution  in  the  size  of  the  thyroid  gland  and  retrogression 
in  the  symptoms  of  hyperthyroidism,  even  to  an  improvement 
in,  or  the  disappearance  of,  exophthalmos. 

Osteomalacia. — This  disease  has  usually  been  attributed 
to  hyperplasia  of  the  ovaries  which    are    normally  concerned    in 


328  THERAPEUTICAL   USES    OF   PITUITARY   EXTRACTS 

the  excretion  of  calcium  from  the  maternal  economy,  and  I  have 
found  hyperplasia  of  the  ovarian  interstitial  cells  in  this  disease1. 
Erdheim2,  however,  has  observed  with  osteomalacia  hyperplasia 
of  the  parathyroids  ;  but  this  is  probably  secondary,  and  is  an 
antagonistic  response  to  the  ovarian  hyperplasia.  Bossi3  believes 
that  the  osteomalacia  is  due  to  insufficiency  of  the  suprarenal 
medullary  secretion. 

Whatever  the  truth  may  be  concerning  the  causal  factors 
in  this  disease,  there  is  no  doubt  that  the  actual  metabolic  dis- 
turbance is  an  excessive  excretion  of  calcium  salts. 

Formerly,  the  ovaries  were  removed  in  the  treatment  of  this 
condition  with  satisfactory  results  in  many  cases.  Then  Bossi 
suggested  the  injection  of  suprarenal  extract,  also  with  satisfactory 
results. 

A  few  years  ago  Kate  Knowles,  who  was  then  in  Kashmir, 
at  my  suggestion  used  infundibulin  in  the  treatment  of  these 
cases  with  very  good  results,  both  in  regard  to  the  relief  of 
pain,  and  the  arrest  of  the  disease. 

Other  conditions  of  imperfect  calcium  retention  in  the 
tissues. — As  we  have  seen,  much  of  the  efficacy  of  continued 
medication  of  pituitary  extracts  is  due  to  the  effect  of  infund- 
ibulin, and  possibly  of  the  extract  of  the  pars  anterior,  on  the 
calcium   metabolism. 

This  power  of  causing  calcium  retention  in  the  tissues  has 
been  utilized  by  Klotz4  in  the  treatment  of  rickets  with  some 
success. 

Some  years  ago  I  was  consulted  in  the  remarkable  case  of  a 
lady  who  suffered  so  severely  from  muscular  and  ligamentary 
weakness  that  she  was  quite  unable  to  walk  and  even  to  hold  a 
pen  with  which  to  write.  This  condition  had  followed  an  arti- 
ficially produced    menopause. 

Prolonged  treatment  with  infundibulin  and  calcium  lactate 
led  to  a  comulete  cure  of  the  serious  disabilities5. 


1  Bell,  W.  Blair,  The  Sex  Complex,  1916. 

2  Erdheim,  J.,  Sitz    d.  k.  Alcad.   d.   Wissench.   Math.-naturw.  Kl.,  Wien,  1907, 
cvvi,  3  Alt,  311. 

3  Bossi,  L.  M.,  Zentralbl.f.  Qynah,  1907,  xxxi,  69. 
*  Klotz,  R.,  Munch.  Med.  Woch.,  1912,  lix,  1145. 

6  Simpson,  A.  Hope,  Liverp.  Med.  Chirurg.  Joum.,  1914,  xxxiv,  357. 


ANTAGONISTIC   AND   METABOLIC   EFFECTS        329 

From  the  foregoing  remarks  concerning  the  therapeutical  uses 
of  pituitary  extracts  it  will  have  been  gleaned  that  much  is 
entirely  empirical  if  not  purely  speculative  ;  and  that  even  in  the 
present  day  our  knowledge  is  only  laid  on  sure  foundations  in 
regard  to  "  the  therapeutical  value  of  the  infundibular  extract  in 
shock,  uterine  atony,  and  intestinal  paresis  " — the  title  of  the 
first  clinical  paper  on  the  subject. 


INDEX 


Abortion,  effects  of  infundibulin  in,  317. 
Accidental  haemorrhage,  effects  of  infundibulin  in,  315. 
Acidophil  cells  in  pars  anterior,  see  Cells,  eosinophil. 
Acromegaly,  219- 

accessory  pars  anterior,  hyperplasia  in,  causing,  234. 

adenocarcinoma  of  pars  anterior  in,  232. 

adenoma  of  pars  anterior  in,  231. 

amenorrhoea  in,  220. 

an  atavism,  230. 

bones,  enlargement  of,  in,  220. 

breathing,  difficulty  of,  in,  225. 

calcium  retention  in,  220. 

chromophobe  cells  in  pars  anterior  in,  232. 

clinoid  processes,  pressure  atrophy  of,  in,  222. 

„  ,,         thickening  of,  in,  222. 

clitoris,  hypertrophy  of,  in,  220. 
colour-vision  in,  226. 
deafness  in,  226. 
diplopia  in,  226. 

dorsum  settee,  thickening  of,  in,  222. 
eosinophil  cells  in  pars  anterior  in,  231. 
epileptiform  seizures  in,  222,  226. 
excretion,  urinary,  in,  229,  230. 
„  calcium,  in,  229. 

„  chlorine,  in,  229. 

„  magnesium,  in,  229. 

„  nitrogen,  in,  229. 

„  phosphorus,  in,  229 

„  potassium,  in,  229. 

„  sodium,  in,  229 

exophthalmos  in,  227. 
extract,  ovarian,  in  treatment  of,  281. 
„        thyroid,  in  treatment  of,  282. 
extremities  in,  215.  224. 
face,  distortion  of,  in,  224. 
features,  alterations  of,  in,  226. 
feet,  enlargement  of,  in,  220. 
gait  in,  226 

genital  organs,  atrophy  of,  in,  220. 
giddiness  in,  226. 
glycosuria  in,  226,  232. 
hair,  alterations  of,  in,  226. 
hands,  enlargement  of,  in,  220. 

„      splaying  of,  in,  224. 
head,  enlargement  of,  in,  220. 
headaches  in,  226. 

hormonopoietic  organs,  implication  of,  in,  220. 
hyperglycemia  in,  226 


332  THE    PITUITARY 

Acromegaly,  incidence  of,  219. 

„  infections  as  etiological  factor  in,  270. 

,,  localized,  222. 

,,  masculinity  in  women  in,  220. 

,,  metabolism  in,  227. 

,,  nails,  alterations  of,  in,  226. 

,,  nerve,  oculomotor,  involvement  of,  in,  226. 

,,  nose,  mucous  membrane  of,  in,  226. 

„  optic  tracts,  involvement  of,  in,  226. 

„  osteoblasts,  hypersensitive,  in,  220. 

„  pars  anterior,  histology  of,  in,  231. 

,,  ,,         ,,  hypertrophy  of,  in,  230. 

,,  „         ,,  type  of  cell  in,  in,  233. 

,,  pathology  of,  232. 

,,  phalanges,  tufting  of  terminal,  in,  224. 

.,  pharynx,  mucous  membrane  of,  in,  226. 

„  as  pluriglandular  syndrome,  234. 

,,  polyuria  in,  226. 

,,  as  precursor  of  hypopituitarism,  233. 

„  prognathism  in,  224. 

,,  psychology  in,  226. 

,,  sella  turcica,  deformation  of,  in,  222. 

,,  „  „        enlargement  of,  in,  222. 

,,  sex-characteristics,  secondary  male,  production  of,  in,  220. 

„  sexuality,  increased,  in,  220,  248. 

„  sinuses,  frontal,  enlargement  of,  in,  222 

,,  skin,  coarseness  of,  in,  220,  226. 

„  ,,     pigmentation  of,  in,  226. 

„  sterility  in,  220. 

„  superciliary  ridge*,  enlargement  of,  in,  222. 

,,  symptoms,  lesions  in  pituitary  as  cause  of,  in,  234. 

„  ,,         signs  and  course  of,  219. 

„  teeth,  separation  of,  in,  226. 

,,  tinnitus  aurium.  in,  226. 

„  tongue,  enlargement  of,  in,  226. 

„  torpidity  in,  226. 

,,  vision  in,  226. 

,,  voice,  deepening  of,  in,  220. 

„  vomiting  in,  226. 

Adenocarcinoma  of  pars  anterior  in  acromegaly,  232. 
Adenoma  of  pars  anterior  in  acromegaly,  231. 
Adiposity,  see  Fat. 
Age,  variations  in  microscopical  appearances  of  pituitary  according  to,  38. 

>»  .-,         in  weight  of  pituitary  according  to,  17. 

Alligator  mississippiensis,  51. 
Amenorrhcea  in  acromegaly,  220. 

,,  effects  of  pituitary  extracts  in,  324. 

,,  in  hypopituitarism,  241. 

Ammocoetes,  40. 
Amphibia,  48. 

Caudata,  49. 

,,        Salamandra  maculosa,  49. 
Ecaudata,  48. 

,,         Bufo  vulgaris,  48. 
,,         Rana  esculenta,  48. 
„         Rana  sylvatica,  48. 
Anaesthesia,  method  of  producing,  in  removal  of  pituitary,  129,  293. 
Anatomy,  comparative,  of  pituitary,  40. 


INDEX  333 

Anatomy   of  pituitary,  14. 

„         „  niacroscopical,  14. 

,,         ,,  microscopical,  28. 

,,         „  „  variations  according  to  age  in,  38. 

„         ,,  surgical,  282. 

Anguilla  vulgaris,  46. 
Anomalies,  anatomical,  284. 

„  ,,  of  cribriform  plate,  285. 

„  „  „  sphenoidal  sinuses,  284,  285. 

Anterior  lobe,  see  Pars  anterior. 
Asthenia,  effects  of  infundibulin  in,  309. 
Aves,  52. 

Baboon,  76. 

Bacteria,  effects  on  pituitary  of  inoculations  with,  207. 

Basophil  cells  in  pars  anterior,  see  Cells,  basophil. 

Bladder,  effect  of  infundibulin  on,  1 10,  322. 

Blindness  in  hypopituitarism,  243. 

Blood-channels  in  pars  anterior  of  ovis  aries,  63. 

,,  ,,      ,,  ,,       ,,     raia  batis,  44. 

,,  ,,      ,,  ,,       ,,    salamandra  maculosa,  49. 

,,  „      „  ,,       ,,    torpedo  marmorata,  44. 

Blood  -pressure,  effects  of  infundibulin  on,  108. 

„  in  hypopituitarism,  241. 

Blood-sinuses  in  pars  anterior,  28. 
Bones,  enlargement  of,  in  acromegaly,  220. 
Bos  taunts,  60. 

Breathing,  difficulty  of,  hi  acromegaly,  226. 
Bufo  vulgaris,  48. 
Bullet- wound  as  cause  of  hypopituitarism,  238, 

Cachexia  hypophyseopriva,  140,  166. 
Calcium  excretion  in  acromegaly,  229. 

,,        metabolism,  effect  of  infundibulin  on,  328. 
,,        retention  in  acromegaly,  220. 
Canis  familiaris,  66. 
Cannula,  uterine,  111. 
Carbohydrate-tolerance  in  experimentally  produced  dystrophia  adiposogenitalis,  166. 

„  ,,         ,,  hypopituitarism,  241. 

Cardiac  rhythm,  effect  of  stimulation  of  pituitary  on,  171. 

,,  ,,  ,,      ,,  infundibulin  on,  106. 

Carnivora,  66. 

Cs&sarean  section,  effect  of  infundibulin  in,  317. 
Cat,  66. 
Gaudata,  49. 
Cavia  familiaris,  65. 
Cells,  acidophil,  in  pars  anterior,  29.     (See  also  Cells,  eosinophil.) 

„     basophil,  hi  pars  anterior,  29,  83,  92. 

„  „  „      „  ,,  in  exophthalmic  goitre,  264. 

„  ,,  ....  ,,  after  inoculation  with  staplvylococci,  207. 

„     chief,  in  pars  anterior,  85. 

,,     chromophil,  hi  para  anterior,  29,  83.     (See  also  Cells,  eosinophil  and  basophil.) 

„     chromophobe,  in  pars  anterior,  29,  83,  92. 

„  ,,  ,,     ,,  ,,        in  acromegaly,  232. 

„  „  ,,     „  „         »,  cretinism,  261. 

„  „  „     „  „        after  inoculations  with  bacteria,  207. 

„  „  ,,     „  ,,        in  parenchymatous  goitre,  264. 

„  „  „     „  ,.        after  removal  of  ovaries,  193. 


334  THE    PITUITARY 

Cells,  chromophobe  in  pars  anterior  after  removal  of  suprarenals,  199. 

,,  „  „     „  ,-.  „  „         „  thyroid,  183,  205. 

,,  ,,  in  pars  intermedia,  33,  95. 

,,     eosinophil,  in  pars  anterior,  29,  83,  92. 

,,  „         „      „  „         in  acromegaly,  231. 

„  ,,         ,,      „  ,,         „  eclampsia,  272. 

,,  ,,         ,,      „  „         after  removal  of  ovaries,  193. 

„  ,,         „      „  ,,  ,,  „        „     suprarenals,  199. 

„      „  „  „  „        „     thyroid,  183, 205. 

„  ,,         ,,      „    intermedia  of  hedgehog,  73. 

,,     hgematoxylinophil,  in  pars  anterior,  29.     (See  also  Cells,  basophil.) 

„     neutrophil,  in  pars  anterior,  29.     (See  also  Cells,  chromophobe.) 

„  „         „      „     intermedia,  33.     (See  also  Cells,  chromophobe.) 

„     pregnancy,  in  pars  anterior,  85. 

,,  „         „      ,,  ,,        in  eclampsia,  272. 

,,  ,,         „      „  „        after  removal  of  thyroid,  183,  205. 

,,     principal,  in  pars  anterior,  85. 

,,     syncytial,  in  pars  anterior,  in  cretinism,  262. 
„         „       „  „       „  lemur,  74. 

„  „        „       „  „       „    pregnancy,  85. 

,,  „         „       „  „       after  thyroidectomy,  185. 

„     wandering,  of  pars  intermedia  in  pars  nervosa,  35,  97. 

„  ,,  „  „  „  „  of  cat,  69. 

„  „  ,,  ,,  „  „  ornithorhynchus,  58. 

„  ,,  „  „  „  „  after  thyroidectomy,  182. 

Cerebrospinal  fluid,  infundibulin  in,  102. 
Chemistry  of  the  pituitary,  101. 
Chief  cells  in  pars  anterior,  see  Cells,  chief. 
Chlorine  excretion  in  acromegaly,  229. 
Chromophil  cells  in  pars  anterior,  see  Cells,  chromophil. 
Chromophobe  cells  in  pars  anterior,  see  Cells,  chromophobe. 
Circulatory  system.;,  effects  of  infundibulin  on,  105,  306. 
Clinoid  processes,  pressure  atrophy  of,  in  acromegaly,  222. 

,,  ,,        thickening  of,  in  acromegaly,  222. 

Clitoris,  hvpertrophy  of,  in  acromegaly,  220. 
Cod,  45. 

Collapse,  effects  of  infundibulin  in,  307. 
Colloid  bodies,  see  Cells,  wandering. 

„      formation  in  pars  anterior,  92. 
Colon  bacillus  inoculations,  effects  of,  on  pituitary,  207. 
Colour-vision  in  acromegaly,  226. 

„  ,,    hypopituitarism,  243. 

Commissure  of  Gudden,  255. 
„  Stilling,  255. 
Comparative  anatomy,  40. 

physiology,  214. 
Contraindications  to  administration  of  pituitary  extracts,  305. 

„  ,,       „  ,,  „  infundibulin  in  obstetric  practice,  319. 

Cortical  necrosis  of  kidneys  causing  changes  in  pituitary,  272. 
Craniopharyngeal  canal,  22,  234. 

Cretinism  causing  secondary  changes  in  pituitary,  262. 
Cribriform  plate,  anatomical  anomalies  of,  285. 
Cyclostomata,  40. 

,,  Pelromyzontes,  40. 

,,  Ammocoztes,  40. 

„  Pelromyzon  Jluvialilis,  41 

Cynocephalus  babuin,  76. 


INDEX  335 


Deafness  in  acromegaly,  226. 

Destruction  of  pituitary,  126. 

Development  of  pituitary;  3. 

Diabetes  insipidus  caused  by  secondary  lesions  of  pituitary,  269. 

,,  „       extracts  of  pituitary  in  treatment  of,  326. 

Didelphys  virginiana,  58. 
Dimensions  of  pituitary,  14. 
Diplopia,  in  acromegaly,  226. 

„         cause  of,  258. 

„         in  hypopituitarism,  243. 
Distal  epithelial  portion,  definition  of,  2.     (See  also  Pars  anterior .) 
Diuresis,  see  Polyuria. 
Dog,  66. 
Dog-fish,  45. 
Dormouse,  65. 
Dystrophia  adiposogenitalis,  see  Hypopituitarism. 

Ecaudata,  48. 

Eclampsia,  causing  changes  in  pituitary,  272. 

Eel,  46. 

Elasmobranchii,  45. 

„  pars  posterior,  absence  of,  in,  43. 

Emboli,  bacterial,  causing  secondary  lesions  of  pituitary,  271. 
Embryonic  rests  as  cause  of  hypopituitarism,  246. 
Endothelioma  as  cause  of  hypopituitarism,  236. 
Eosinophil  cells  hi  pars  anterior,  see  Cells,  eosinophil. 
Epileptiform  seizures  in  acromegaly,  222,  226. 
„  ,,         „  hypopituitarism,  243. 

Ennaceus  europceus,  71. 
Excretion,  calcium,  in  acromegaly,  229. 
„        chlorine,  in  acromegaly,  229. 
„         magnesium,  in  acromegaly,  229 
„        nitrogen,  in  acromegaly,  229. 
„        phosphorus,  in  acromegaly,  229. 
,,         potassium,  in  acromegaly,  229. 
„         sodium,  hi  acromegaly,  229. 
,,        urinary,  in  acromegaly,  229,  230. 
Exophthalmic  goitre,  see  lly\»  rthyroidism. 
Exophthalmos  in  acromegaly,  227. 
Extirpation  of  pituitary,  145. 

„         „        „  with  implantation  of  grafts,  170. 

„        „         „  results  of,  164. 

Extracranial  methods  of  operation,  291. 
Extract,  duodenal,  effect  on  pituitary  of,  110,  177. 
„        ovarian,  in  hyperpituitarism,  281. 
,,       pituitary.     (See  also  Infundibuhn.) 
„  „         in  amenorrhcea,  324. 

,,  „         antagonistic  and  metabolic  effects  of,  327. 

.,  ,,        contraindications  to  use  of ,  305. 

dry,  302. 
„  ,,         in  dystrophia  adiposogenitalis,  324. 

„  „         effects  produced  by,  105,  306. 

„  „         in  hypoplasia  of  ovaries,  326. 

„  „        „  „         „  thyroid,  326. 

„  ,,         indications  for  administration  of,  304. 

„  „         liquid,  302. 

,,  „         manufacture  of,  303. 

„  „         methods  of  administration  of,  303. 


336  THE    PITUITARY 

Extracts,  pituitary,  strengths  of,  302. 

„  ,,         substitution  and  supplementary  effects  of,  324. 

„  ,,         supplementation  with,  180. 

,,  thyroid,  in  hyperpituitarism,  282. 

Extremities,  in  acromegaly,  215,  224. 

,,  tapering,  in  hypopituitarism,  244. 

Face,  distortion  of,  in  acromegaly,  224. 

Fat,  deposition  of,  after  compression  of  the  stalk,  158. 

,,  ,,  „       „     separation  of  the  stalk,  158. 

,,  ,,  ,,     in  hibernation,  87. 

„  ,,  ,,      „  hypopituitarism,  236,  241. 

Features,  alterations  in,  in  acromegaly,  226. 
Feet,  enlargement  of,  in  acromegaly,  220. 
Felis  domestica,  66. 
Fits  in  hypopituitarism,  244. 
Formamine,  see  Hexamethylenamine. 
Fowls,  brooding,  pars  anterior  in,  83. 

Gadus  morrhua,  45. 
Gait  in  acromegaly,  226. 
Gallus  clomesticus,  52. 

Genital  organs,  after  combined  partial  removal  of  the  partes  anterior  and  posterior, 
157. 
„  „  „    removal  of  the  pars  posterior,  153,  195. 

,,  ,.        atrophy  of,  after  compression  of  stalk,  158. 

„  ,,  ,,         „      ,,      partial  removal  of  pars  anterior,  150,  165,  195. 

„  ,,  ,,         .,      „     separation  of  stalk,  158. 

„  „  „         ,,    in  acromegaly,  220. 

„  „  „         „     ,,  hypopituitarism,  236,  241. 

Glycogenolytic  substance  in  pars  posterior,  109,  140,  177. 
Glycosuria  in  acromegaly,  226,  232. 

,,         caused  by  artificial  tumours,  172. 

,,  „      „     experimental  operations  on  pituitary,  140,  169. 

„  „      ,r     faradization  of  pituitary,  171. 

,,  ,,      ,,     indirect  stimulation,  175. 

Goitre,  exophthalmic,  causing  secondary  lesions  of  pituitary,  264. 

„      parenchymatous,  causing  secondary  lesions  of  pituitary,  264. 
Gonads,  affections  of,  in  primary  lesions  of  pituitary,  248. 

,,        lesions  of,  causing  secondary  lesions  of  pituitary,  266.     (See  also  Genital 
organs.) 
Graafian  follicles,  atrophy  of,  after  partial  removal  of  pars  anterior,  196 
,,  ,,  ,,         „        ,,     compression  of  stalk,  196. 

„  ,,  ,,         „        „     separation  of  stalk,  196. 

Grafts,  extirpation  with  implantation  of,  170. 

,,       immediate  results  of,  120. 
Guinea-pig,  65. 
Gustatory  phenomenon  hi  hypopituitarism,  244. 

Hsematoxylinophil  cells  in  pars  anterior,  29.     (See  also  Cells  basophil.) 
Haemorrhage,  accidental,  treatment  with  infundibulin  in,  315. 
Hair,  alterations  of,  in  acromegaly,  226. 

,,     loss  of,  in  hypopituitarism,  244. 
Hands,  enlargement  of,  in  acromegaly,  220. 

„       splaying  of,  in  acromegaly,  224. 
Head,  enlargement  of,  in  acromegaly,  220. 
Headache,  pituitary,  in  acromegaly,  226,  288. 

,,  ,,  ,,  ,,  an  indication  for  operation,  286. 

„  „  ,,  ,,  surgical  treatment  of,  297. 


INDEX 


337 


Headache,  pituitary,  in  hypopituitarism,  243. 

,,  after  administration  of  pituitary  extract,  325. 

Heart,  effect  of  infundibulin  on  rhythm  of,  106. 
Hedgehog,  71. 

Hemiachromatopia,  cause  of,  255. 
Hemianopia  in  acromegaly,  226. 

„  „  hypopituitarism,  243. 

,,  bitemporal,  cause  of,  255,  257. 

Hexamethylenamine  in  the  preparation  for  operation,  129,  286. 
Hibernation,  dystrophia  adiposogenitalis,  87. 
„  pituitary  in,  85. 

„  pluriglandular  inactivity  in,  85. 

Hormonopoietic  organs,  affections  of,  causing  secondary  lesions  in  pituitary,  262. 
,,  „       effects  of  diseases  of,  211. 

,,  ,,       implication  of,  in  acromegaly,  220. 

„  „       interrelation  of,  with  pituitary,  182. 

,,  ,,       results  of  removal  of,  on  pituitary,  182. 

„  „  „  „  ,,  pituitary  on,  204. 

Hour-glass  contraction  of  uterus  after  use  of  infundibulin,  318. 
Hyaline  bodies  in  pars  nervosa,  see  Cells,  wandering. 
Hydrocephalus  as  cause  of  hypopituitarism,  245. 

„  „       „     ,,    secondary  lesions  of  pituitary,  259. 

Hyperglycemia,  124,  226. 
Hyperhypophysism ,  see  Acromegaly. 
Hyperpituitarism,  see  Acromegaly. 
Hyperplasia  of  pituitary,  effects  of,  in  adult  life,  219. 
„     „     „    early  life,  219. 
Hyperthyroidism,  effects  of  infundibulin  on,  327. 

„  causing  secondary  changes  in  pituitary,  264. 

Hypoglycemia,  241. 
Hypophysial  angle,  3. 
Hypohypophysism,  see  Hypopituitarism. 
'  Hypophysis  ',  definition  of,  2. 
Hypopituitarism,  236. 

acromegaly  as  precursor  of,  233. 

amenorrhoea  in,  241. 

blindness  in,  243. 

blood -pressure  in,  241. 

bullet-wound  as  cause  of,  238. 

carbohydrate-tolerance  in,  241. 

colour-vision  in,  243,  244. 

compression  of  stalk  causing.  159. 

diplopia  in,  243. 

dystrophia  adiposogenitalis  after  puberty  in,  241. 

,,  „  before  puberty  in,  241. 

embryonic  rests  as  cause  of,  246. 
endothelioma  in,  236. 
epileptiform  seizures  in,  243. 
extracts,  pituitary,  in,  324. 
extremities,  tapering,  in,  244. 
glandular  administration  in,  280. 
gustatory  phenomenon  in,  244. 
hair,  loss  of,  in,  244. 
headaches  in.  21."!. 
hemianopia  in,  243. 
hibernation  resembling,  87. 
hydrocephalus  as  cause  of,  244. 
hypoglycemia  in,  241. 

22 


338  THE   PITUITARY 

Hypopituitarism,  infantilism  in,  236. 

„  irritability  in,  243. 

„  lassitude  in,  241. 

„  Lorain  type  of  infantilism  in,  236. 

„  menstruation,  scanty,  in,  241. 

,,  memory,  loss  of,  in,  244. 

,,  obesity  in,  241. 

,,  olfactory  phenomenon  in,  244. 

„  overgrowth  with  adiposity  and  genital  inactivity  in,  236. 

„  pars  anterior,  atrophy  of,  in,  247. 

„  pathology  of,  244. 

„  pituitary  extracts  in,  324. 

psychology  in,  243. 

„  puberty,  after,  241. 

,,  ,,       before,  236. 

„  scanty  menstruation  in,  241. 

„  sella  turcica  in,  236. 

„  ,,         „       deformation  of,  in,  243. 

„  separation  of  stalk  causing,  159. 

,,  sex-characteristics,  secondary  female,  production  of,  in,  249. 

„  sexual  infantilism  in,  236. 

„  skin,  smooth,  in,  244. 

,,  sterility  in,  241. 

„  stunted  growth  with  sexual  infantilism  and  adiposity  in,  236. 

„  subnormal  temperature  in,  241. 

„  symptoms  and  incidence  of,  226. 

„  thermic  reaction  in,  166,  241. 

„  torpidity  in,  243. 

„  types  of,  occurring  after  puberty,  240. 

„  „     ,,             ,,        before  puberty,  236. 

„  ,,     feminine  in,  241. 

,,  vision  in,  243. 

„  ,,     colour,  in,  243. 

„  vomiting  in,  246. 

Incidence  of  acromegaly,  219. 

,,         „   hypopituitarism,  236. 
Indications  for  administration  of  pituitary  extracts,  304. 

„  ,,  operation,  286. 

Induction  of  labour,  effects  of  infundibulin  on,  311. 
Infantilism,  after  experimental  operations  on  the  pituitary,  165. 
„  in  hypopituitarism,  236. 

„  Lorain  type  of,  in  hypopituitarism,  236. 

,,  sexual,  in  hypopituitarism,  236. 

„  „       with  stunted  growth,  and  adiposity  in  hypopituitarism,  236. 

Infections  causing  hyperplasia  of  pituitary,  270. 

„  ,,  ,.  ,,         „  with  increase  in  skeletal  growth,  271. 

„  „       necrosis  of  pituitary,  271. 

„  „       secondary  lesions  of  hypophysis,  270. 

„         effects  of  experimentally  produced,  211. 
,,  „      ,,   generalized,  in  Man,  270. 

„  ,,      „   localized,  in  Man,  270. 

Infundibular  process,  development  of,  9. 
Infundibulin,  absorption  of,  105. 

„  action  of  pepsin  on,  101. 

,,  ,,      ,,  trypsin  on,  101. 

„  in  cerebrospinal  fluid,  102. 

„  definition  of,  2 


INDEX 


339 


Infundibulin,  ingestion  of,  105. 

,,  injection  of,  105. 

»  »>       -.,    intravenous,  immediate  results  of,  105. 

a  »        »  jj  „  „       „  on  alimentary  tract,  112. 

"  »        »  59  jj  „      ,,    ,,    blood -pressure,  108. 

"  J9       »  j>  9>  ,,      ,,    ,,    bladder,  110. 

"  »        »s  >»  jj  „       „    „     cardiac  rhythm,  106, 

"  !>       j»  59  55  9;      „    ,y    cerebrospinal    secre- 

tion, 103. 

"  99        9;  ;,  „  ,,      „    ,,    circulatory    system, 

105. 

"  99       9?  j,  „  „      „    „    dilator    muscles    of 

iris,  119. 

"  99        59  95  99  95      9;     -5     intestines,  112, 

55  99       99  5s  „  „      „     „     kidneys,  109. 

95  99        99  95  ,5  „      „     „     mammary      glands, 

114. 

55  -j       59  55  55  95      95     55     pancreatic  secretion, 

119. 

55  55        55  55  55  >,      „     „     pulmonary  arteries, 

108. 

59  5.        99  55  55  ,,     ,5     55     respiratory    system, 

109. 

95  55  99  99  55  55  55  55         Spleen,    108. 

99  59        99  99  99  ,,      „     ,,     stomach,  114. 

»  59        99  99  55  ,,     „     „     urinary  system,  109. 

«  99       99  95  55  „     ,,     „     uterus,  111. 

•j  „        „    repeated,  106. 

„  origin  of,  96. 

„  pressor  effects  of,  306. 

„  ,,    in  abortion,  317. 

,,  ,,    ,,  accidental  haemorrhage,  315. 

„  ,,    on  alimentary  tract,  321. 

„  „    in  asthenia,  309. 

„  ,,    on  bladder,  322. 

,,  ,,    in  Caesarean  section,  317. 

„  „    on  circulatory  system,  306. 

.,  ,,    in  collapse,  307. 

„  „    contraindications  to  use  of,  in  obstetric  practice,  319. 

„  „    in  diabetes  insipidus,  326. 

,,  ,,    gynaecological  uses  of,  320. 

„  „    hour-glass  contraction  of  uterus  after  use  of,  318. 

„  „    in  hyperthyroidism,  327. 

„  „    ill  effects  of,  in  obstetric  practice,  318. 

,,  ,,    in  induction  of  labour,  311. 

„  ,,    on  kidneys,  321. 

„  ,,    ,,  mammary  glands,  322. 

,,  ,,    in  menopausal  flushings,  309. 

„  „    ,,   monorrhagia,  320. 

,,  „    ,,  osteomalacia,  327. 

„  ,,    obstetrical  uses  of,  310. 

„  „    in  paralytic  distention  of  stomach  and  intestine,  321. 

„  ,,    ,,  placenta  previa,  315. 

„  „    „  post  partum  haemorrhage,  317. 

,,  ,,    rigidity  of  cervix  after  use  of,  318. 

,,  ,,    in  sepsis,  308. 

„  ,,    „  serum-sickness,  308. 
„    „   shock,  306. 


340 


THE   PITUITARY 


Infiindibulin,  pressor  effects  of.  on  spleen,  323. 

„       ,,    in  subinvolution,  317. 
„       „    tetanic  spasms  after  use  of,  319. 
„       „    on  urinary  system,  321. 
„       ,.    in  uterine   inertia,  primary,  314. 
,,       „    „         ,,  ,,       secondary,  314. 

,,       ,,    on  uterus,  310. 
.,       „    uterus,  rupture  of,  after  use  of,  318. 
,,  toxic  effects  of,  123. 

Ingestion  of  pituitary  extracts,  late  results  of,  122. 
Injections  of  pituitary  extracts,  late  results  of,  122. 

„         intravenous,  of  infundibulin,  immediate  results  of,  105. 
,,         repeated,  of  infundibulin,  effects  of,  106. 
Jnseclivora,  71. 

Interstitial  cells,  degeneration  of,  after  partial  removal  of  pars  anterior,  196. 
„  „  ,,  ,,         „     compression  of  the  stalk,  196. 

„  ,,  ,,  ,,         ,,     separation  of  the  stalk,  196. 

Intestines,  effect  of  infundibulin  on,  112. 

,,  paralytic  distension  of,  effects  of  infundibulin  on,  321. 

Intracranial  methods  of  operation,  287. 
Iris,  dilator  muscles  of,  effect  of  infundibulin  on,  119. 
Irritability  in  hypopituitarism,  243. 

Juxtaneural  epithelium,  definition  of,  2. 

,,  „  one  layer  of,  in  opossum,  59. 

(See  also  Pars  intermedia.) 

Kidneys,  effects  of  infundibulin  on,  109,  321. 

,,         cortical  necrosis  of,  causing  changes  in  pituitary,  272. 

Lacerta  viridis,  51. 

Lassitude  in  hypopituitarism,  241. 

Lemur,  73. 

Lemur  catta,  73. 

Lemuridce,  73. 

Lepus  cuniculvs,  65. 

Lesions  of  pituitary,  primary,  218. 

,,  coincidental,  and  suprarenals,  249. 

,,  gonads,  affections  of,  in,  248. 

,,  nerve,  fourth,  paresis  of,  in,  258. 

,,  „      sixth,  paresis  of,  in,  258. 

,,  „      third,  paresis  of,  in,  258. 

„  nystagmus  in,  258. 

,,  oj)tic  tracts,  injuries  to,  in,  255. 

„  pineal,  affections  of,  in,  251. 

„  producing  no  pituitary  symptoms,  253. 

,.  vision,  disturbances  of,  in,  226,  243,  253. 

„  suprarenals,  affections  of,  in,  249. 

,,  thymus,  affections  of,  in,  250. 

„  thyroid,  affections  of,  in,  250. 
secondary,  259. 

,,  bacterial  emboli  causing,  271. 

„  cretinism  causing,  262. 

„  diabetes  insipidus  caused  by,  269. 

.,  dystrophia  adiposogenitalis  caused  by,  269. 

,,  exophthalmic  goitre  causing,  264. 

„  gonads,  lesions  of,  causing,  266. 

,,  hormonopoietic  organs,  affections  of  causing,  262. 


INDEX  341 

Lesions  of  pituitary,  secondary,  hjTdrocephalus  causing,  259. 
„  ,,  „  infections  causing,  270. 

,,  „  ,,  metastases  causing,  269. 

„  ,,  „  niyxoedema  causing,  264. 

„  „  „  neighbouring  pathological  conditions  causing,  259. 

„  „  ,,  pancreas,  lesions  of,  causing,  268. 

„  ,,  „  parenchymatous  goitre  causing,  264. 

.,  ,,  „  suprarenals,  lesions  of,  causing,  268 

„  ,,  ,,  thymus,  lesions  of,  causing,  267 

,,  „  „  thyroid,  lesions  of,  causing,  262. 

Lipoid  particles  in  pars  anterior,  93. 
Lobe,  anterior,  see  Pars  anterior. 
„     lateral,  of  Ecaudata,  49. 
,,     middle,  of  petromyzon  fluviatilis,  41. 
,,      posterior,  definition  of,  2. 
,,  „        extract  of,  2,  302. 

Lobus  infundibuli  of  petromyzon  fluviatilis,  41. 
Localized  acromegaly,  222. 

Lorain  type  of  infantilism  in  hypopituitarism,  236. 
Lumbar  puncture  in  preparation  for  operation,  287. 
Lymphatics  of  pars  anterior,  32. 

„  ,,       ,,    intermedia,  34. 

Macacus  rhesus,  75. 
Macula,  255. 

Maculopapillary  bundle,  255. 
Magnesium  excretion  in  acromegaly,  229. 
Mammalia,  55. 

„        Carnivora,  66. 

„  ,,       Felis  domestica,  66. 

„  „       Canis  familiaris,  66. 

„        Insectivora,  71. 

„  „         Erinaceus  europceus,  71. 

„        Man,  76. 

„        Marsupialia,  58. 

„  „  Didelphys  mrginiana,  58. 

5,        Monotremata,  55. 

.,  „  Ornithorhynchus  anatinus,  55. 

„        Primates,  73. 

,j  „  Cynocephalus,  76. 

„  „  Lemur  catta,  73. 

„  ,,  Macacus  rhesus,  75. 

„  „  Simiidce,  75. 

„        Rodentia,  65. 

„  „  Muscurdinus  avcllanarius,  65. 

„  „  Cavia  familiaris,  65. 

„  ,,  Lepus  auriculas,  65. 

„  „  M us  domestic  us,  65. 

„        Ungulata,  60. 

.,  „         Bos  taunts,  60. 

„  „  Ovis  aries,  61. 

,,  „  Sus  domesticus,  61. 

Mammary  glands,  effect  of  infundibulin  on,  114,  322. 
Man,  76. 
Marswpialia,  58. 

Masculinity  in  women  in  acromegaly,  220. 

Measurements,  surgical  and  anatomical,  in  regard  to  sella  turcica,  284. 
Memory,  loss  of,  in  hypopituitarism,  244. 


342  THE   PITUITARY 

Menopausal  flushings,  effects  of  infundibulin  on,  309. 

Menorrhagia,  effects  of  infundibulin  on,  320. 

Menstruation,  scanty,  in  hypopituitarism,  241. 

Metabolism  in  acromegaly,  227. 

Metastases,  causing  secondary  lesions  of  pituitary,  269. 

Monkeys,  75. 

Monotremata,  55. 

Morphology  of  pituitary,  3. 

Muscardinus  avellanarius,  65. 

Mus  domesticus,  65. 

Myxoedema  causing  secondary  lesions  of  hypophysis,  264. 

Nails,  alterations  of,  in  acromegaly,  226. 
Nasal,  inferior,  routes  in  operations,  291. 

„     superior,  routes  in  operations,  291. 
Necrosis,  cortical,  of  kidneys  causing  changes  in  pituitary,  272. 

„       of  pituitary,  infections  causing,  271. 
Nerve,  fibres,  sympathetic,  in  pars  anterior,  32. 

„     fifth,  ophthalmic  division  of,  24. 

„     fourth,  24. 

„  ,,       paresis  of,  258. 

„     sixth,  paresis  of,  258. 

„     third,  24. 

„  „     (oculomotor),  involvement  in  acromegaly,  226. 

„  „     paresis  of,  258. 

Neuroglia-cells  of  pars  nervosa,  36. 
Neutrophil  cells  in  pars  anterior,  see  Cells,  neutrophil. 
Nitrogen  excretion  in  acromegaly,  229. 
Nose,  mucous  membrane  of,  in  acromegaly,  226. 
Nystagmus  in  lesions  of  pituitary,  258. 

Obesity  in  hypopituitarism,  241. 
Obstetrical  uses  of  infundibulin,  310. 
Oculomotor  nerve,  see  Nerve,  third. 
Olfactory  phenomenon  in  hypopituitarism,  244. 
Operations,  experimental,  on  pituitary,  126. 

„  ,,         „  procedures  in,  80. 

buccopharyngeal  route  in,  298. 
extracranial  methods  in,  291. 

hexamethylenamine  in  the  preparation  of  patient  for,  286. 
indications  for,  286. 
intracranial  methods  in,  287. 

lumbar  puncture  in  preparation  of  patient  for,  287. 
nasal  (transphenoidal)  routes  in,  291. 

„  „  „       ,,    inferior,  292. 

„  „  ,,       ,,    submucous  resection  in,  293. 

„  ,,  ,,       .,    superior,  291. 

orbital  and  orbitonasal  routes  in,  298. 
orbitofrontal  route  in,  289. 
overhanging-brain  position  in,  287. 
preparation  of  patients  for,  286. 
results  of,  299. 

selection  of  route  of  approach  in,  286. 
temporal  and  bitemporal  routes  in,  288. 
Opossum,  58. 
Optic  chiasma,  24,  255. 

»  ,,        anatomy  of,  254. 

"  5,        injuries  to,  in  primary  lesions  of  hypophysis,  255. 


INDEX  343 

Optic  chiasma,  involvement  of,  in  acromegaly,  266. 
Orbital  and  orbitonasal  routes,  298. 
Orbitofrontal  route,  289. 
Ornithorhynchvs  anatinus,  55. 
Osteoblasts,  hypersensitive,  in  acromegaly,  220. 
Osteomalacia,  effect  of  infundibulin  in,  327. 
Ovarian  extracts  in  hyperpituitarism,  281. 
Ovaries,  effects  of  compression  of  stalk  on,  196. 

„  ,,       ,,  partial  removal  of  pituitary  on,  195. 

,,  „       ,,  removal  of,  on  pituitary,  192. 

„  ,,      „  separation  of  stalk  on,  196. 

,,       hypoplasia  of,  effects  of  pituitary  extracts  on,  326. 
Overgrowth  with  adiposity  and  genital  inactivity  in  hypopituitarism,  236t 
Overhanging-brain  position  in  operations,  287. 
Oris  aries,  61. 
Ox,  60. 

Pancreas,  infundibulin,  effects  of,  on  secretion  of,  119. 

,,        lesions  of,  causing  secondary  lesions  of  hypophysis,  268. 
,,        pituitary,  relationship  to,  203. 
Parahypophysis,  vascular  supply  of,  26. 

Parenchymatous  goitre  causing  secondary  lesions  of  hypophysis,  264. 
Pars  anterior,  atrophy  of,  in  hypopituitarism,  24.7. 

„  „         ,,  uterus  after  partial  removal  of,  146. 

,,        blood-channels  in,  44,  49,  63. 

,,        blood-sinuses  in,  28. 

„        in  brooding  fowls,  87. 

„        changes  in,  in  acromegaly,  231. 

„        chief  cells  in,  85. 

„        chromophil  cells  in,  85. 

„        chromophobe  cells  in,  85. 

.,        colloid  formation  in,  92. 

„        definition  of,  2. 

„        effects  of  removal  of  ovaries  on,  192. 

„  ,,       ,,         „         „  suprarenals  on,  198. 

,,  ,,       „         „        ,,  thyroid  on,  182. 

„        in  hibernation,  85. 

,,        histological  anatomy  of,  32,  83. 

„        hyperplasia  in  accessory,  causing  acromegaly,  234. 

„        hypertrophy  of,  in  acromegaly,  230. 

„       lipoid  particles  in,  93. 

„       lymphatics  of,  32. 

„        neutrophil  cells  in,  85. 

,,        in  pregnancy,  83. 

„        principal  cells  in,  85. 

„        removal  of,  145. 

„       secretion  of,  91. 

„        significance  of  types  of  cells  in,  89. 

,,        somnolence  after  removal  of,  148. 

„        sympathetic  nerve-fibres  in,  32. 

„        syncytial  confluence  of  cells  in,  85. 

„        trabecule  in,  of  sheep,  61. 

„        types  of  cells  in,  89. 

„        type?  of  cells  in,  in  acromegaly,  233. 
intermedia,  33. 

„  definition  of,  2. 

„  effects  of  removal  of  ovaries  on,  192. 

.»  „       ,,         ,,         ,,  thyroid  on,  189. 


344  THE   PITUITARY 

Pars  intermedia,  effects  of  removal  of,  on  suprarenals,  198. 
„  histology  of,  94. 

„  lymphatics  of,  24. 

nervosa,  35. 

channelling  by  pars  intermedia  of,  in  ornitliorhynclius  anatinus,  56. 
definition  of,  2. 

effects  of  removal  of  ovaries  on,  192. 
„       „        „        ,,  suprarenals  on,  198. 
,,       „         ,,        „  thyroid  on,  189. 
histology  of,  95. 

,,         „     hyaline  bodies  in,  97. 
„  „  ,,  ,,       ,,  destination  of,  97. 

neuroglia-cells  of,  36. 
pigment  in,  37. 
posterior,  absence  of,  in  Elasmobranchii,  43. 
„         definition  of,  2. 
„         extract  of,  see  Infundibulin. 
Pathological  conditions,  neighbouring,  as  cause  of  secondary  lesions  in  pituitary,  259. 

„         processes,  interpretation  of,  211. 
Pathology  of  acromegaly,  232. 

,,  „  hypopituitarism,  244. 

„  ,,  pituitary,  histological  facts  concerning,  215. 

Pathophysiological  investigations,  126. 

„  methods,  80. 

Pepsin,  action  of,  on  infundibulin,  101. 
Petromyzon  fluviatilis,  41. 
Petromyzonles,  40. 

Phalanges,  tufting  of  terminal,  in  acromegaly,  224. 
Pharynx,  mucous  membrane  of,  hi  acromegaly,  226. 
Phosphorus  excretion  in  acromegaly,  229. 
Physiological  investigations,  82. 

„  methods,  79. 

Physiology  of  the  pituitary,  79. 

„  ,,     ,,  „         comparative,  214. 

Pig,  61. 

Pigment  in  pars  nervosa,  37. 

Pineal,  affections  of,  in  primary  lesions  of  hypophysis,  251 . 
Pisces,  41. 

„        Elasmobranchii,  45. 
,,  „  Raia  batis,  43. 

„  „  Squalus  acanthias,  45. 

„  „  Torpedo  marmorata,  44. 

„        Teleostei,  45. 

,,  „  Anguilla  vulgaris,  46. 

„  ,,         Gadus  morrhud,  45. 

'  Pituitary  ',  derivation  of,  1. 
Placenta  prsevia,  effects  of  infundibulin  in,  315. 
Pluriglandular  affections  in  primary  hypophysial  lesions,  248. 

,,  syndrome,  acromegaly  as,  234. 

Polyuria  in  acromegaly,  226. 

„         „  diabetes  insipidus,  treatment  of,  326. 
,.        after  experimental  operations  on  pituitary,  140,  169,  171. 
,,  ,,    grafting  of  the  pars  posterior,  121. 

„  „    injections  of  extracts  of  pars  posterior,  109. 

,,        caused  by  metastases  in  the  pituitary,  269. 
Posterior  lobe,  definition  of,  2. 

„         ,,      partial  removal  of,  153. 
,,         „      total  removal  of,  153. 


INDEX  345 

Postoperative  symptoms  after  removal  of  pituitary,  140. 
Postpartum  haemorrhage,  effects  of  infundibulin  on,  317. 
Potassium  excretion  in  acromegaly,  229. 
Pouch  of  Rathke,  4. 
,,      „  Seessel,  4. 
Pregnancy,  disorders  of,  effects  of,  on  pituitary,  211. 

,,  pars  anterior  in,  83. 

„  cells,  see  Cells,  pregnancy. 

Preparation  of  patient  for  operation,  286. 
Primates,  73. 

Primordial  ova,  degeneration  of,  after  partial  removal  of  pars  anterior,  196. 
Principal  cells  in  pars  anterior,  see  Cells,  'principal. 
Prognathism  in  acromegaly,  224. 
Psychology  in  acromegaly,  226. 

,,  „  hypopituitarism,  243. 

Pulmonary  arteries,  effects  of  infundibulin  on,  108. 

Rabbit,  65. 

IiarJieittlorhln/pophyse,  8. 
Raia  batis,  43. 
Rana  esculenta,  48. 
„     sylvatica,  48. 
Rat,  65. 

Recessus  hypophyseus,  of  petromyzon  fluviatilis,  41. 
Removal  of  pituitary,  127. 

,,         ,,         „  control  experiments  in  regard  to,  140. 

„         ,,         „         method  of  producing  anaesthesia  in,  129. 
,,         ,,         ,, .        operative  technique  in,  129. 
,,         „         ,,         postoperative  symptoms  after,  140. 
,,         ,,         ,,         preliminary  procedures  in,  129. 
„         ,,         „         surgical  procedures  in,  131. 

,,         ,,         ,,  (See  also  Pars  anterior  and  Pars  posterior,  removal  of.) 

Reptilia,  51. 

„        Alligator  mississippiensis,  51. 
„        Lacerta  viridis,  51. 
„         Testudo  europcea,  52. 
„        Testudo  grceca,  52. 
Respirator}'  system,  effects  of  infundibulin  on,  109. 
Results  of  experimental  extirpation  of  pituitary  and  injury  of  stalk,  164. 

„       „  surgical  operations,  299. 
Rhythm,  cardiac,  effect  of  infundibulin  on,  106. 
Rigidity  of  cervix  after  use  of  infundibulin,  318. 
Ring-tailed  lemur,  73. 
Rodentia,  65. 

Routes  of  approach,  selection  of,  286. 
„      buccopharyngeal,  298. 
„      nasal  inferior,  291. 
„  ,,    superior,  291. 

,,      orbital  and  orbitonasal,  298. 
„      orbit  of  rontal,  289. 
,,      temporal  and  bitemporal,  288. 
Rupture  of  uterus  after  use  of  infundibulin,  318. 

Saccus  vascuhsus,  45. 

,,  ,,        function  of,  45. 

,,  ,,        structure  of,  45. 

Salamandra  maculosa,  49. 
Scotoma,  central,  cause  of,  255. 


346  THE   PITUITARY 

Secretion-bodies,  see  Cells,  wandering. 
Sella  turcica,  18. 
„  „        craniopharyngeal  canal,  in  relation  to,  22, 

„  „        deformation  of,  in  acromegaly,  222. 

,,  „  „  „     ,,  hypopituitarism,  24)5. 

„  ,,         enlargement  of,  in  acromegaly,  222. 

„  „         in  hypopituitarism,  236. 

„  ,,         nerve,  fourth,  in  relation  to,  24. 

,,  „  ,,      fifth,  ophthalmic  division  of,  24. 

„  ,,  ,,      sixth:  in  relation  to,  24. 

„  „  „      third,  in  relation  to,  24. 

„  ,,         measurements  in  regard  to,  284 

,,  ,,         optic  chiasma,  in  relation  to,  22. 

,,  „         sphenoidal  cells,  in  relation  to,  22. 

Sepsis,  effects  of  infundibulin  in,  308. 
Serum-sickness,  effects  of  infundibulin  in,  308. 
Sex-characteristics,  secondary,  production  of,  in  acromegaly,  220. 

„  „  „  ,,  ,,     ,,  hypopituitarism,  249. 

Sexual  infantilism  in  hypopituitarism,  236. 
Sexuality,  increased,  in  acromegaly,  220,  248. 
Sheep,  61. 

Shock,  effects  of  infundibulin  in,  306. 
Simiidce,  75. 
Sinuses,  frontal,  enlargement  of,  in  acromegaly,  222. 

,,        sphenoidal,  see  Sphenoidal. 
Skate,  43. 

Skeletal  growth,  infections  causing  hyperplasia  of  pituitary  with,  271. 
Skin,  coarseness  of,  in  acromegaly,  220,  226. 
„     pigmentation  of,  in  acromegaly,  226. 
,,     smooth,  in  hypopituitarism,  244. 
Sodium  excretion  in  acromegaly,  229. 
Somnolence,  see  Torpidity. 
Sphenoidal  cells  in  relation  to  sella  turcica,  22. 

„  sinuses,  anatomical  anomalies  of,  284. 

Spleen,  effects  of  infundibulin  on,  108,  323. 
Squalus  acanthias,  45. 
Squint,  external,  cause  of,  258. 
Stalk  of  pituitary,  compression  and  separation  of,  158. 

„     „  „  ,,  „  ,,         ,,   dystrophia  adiposogenital,  caused 

by,  159. 
„     „  ,,        results  of  injury  to,  164. 

Staphylococcus  inoculations,  effect  of,  on  pituitary,  207. 
Sterility  in  acromegaly,  220. 

„        ,,  hypopituitarism,  241. 
Stimulation  of  pituitary  in  situ,  170. 

„  „         „  „         direct,  171. 

„  „         ,,  ,,  ,,        artificial  tumours  causing,  171. 

,,  „         ,,  ,,  „        faradization  causing,  171. 

„  ,,        ,,  ,,  .,       glycosuria  caused  by,  172. 

,,  ,,        ,,  .,         indirect,  175. 

,,  ,,        ,,  ,,  >>  glycosuria  caused  by,  175. 

„  „        ,,  ,,  ,,  of  superior  cervical  ganglion,  175. 

Stomach,  effects  of  infundibulin  on,  114. 

,,        paralytic  distension  of,  effects  of  infundibulin  on,  321. 
Strengths  of  pituitary  extracts,  302. 
Streptococcus  inoculations,  effects  of,  on  pituitary,  209. 

Stunted  growth  with  sexual  infantilism  and  adiposity  hi  hypopituitarism,  236. 
Subinvolution,  effects  of  infundibulin  on,  317. 


INDEX  347 

Subnormal  temperature  in  hypopituitarism,  241. 
Superciliary  ridges,  enlargement  of,  in  acromegaly,  222. 
Supplementation  with  pituitary  extracts,  180. 
Suprarenals,  affections  of,  in  primary  lesions  of  hypophysis,  249. 

„  effects  of  removal  of,  on  pituitary,  198. 

„  ,,      „         „         ,,    pituitary  on,  198. 

„  lesions  of,  causing  secondary  lesions  of  hypophysis,  268. 

Surgical  anatomy,  282. 

,,      treatment  of  pituitary  lesions,  282. 
Sus  domesticus,  61. 

Sympathetic  nerve-fibres  of  pars  anterior,  32. 
Symptoms  of  acromegaly,  219. 

,,         ,,  hypopituitarism,  236. 

,,        lesions  in  pituitary  as  cause  of,  in  acromegaly,  234. 
S  yncyt ial  cells  in  pars  anterior,  see  Cells,  syncytial. 

Technique,  operative,  in  experimental  removal  of  pituitary,  129. 

„  ,,         „  surgical  operations  on  pituitary,  282. 

Teeth,  separation  of,  in  acromegaly,  226. 
Teleostei,  45. 

Temporal  and  bitemporal  routes  for  operation,  288. 
Testudo  europcea,  52. 

„       grceca,  52. 
Tetanic  spasms  after  use  of  infundibulin,  319. 
Thermic  reaction  in  experimentally  produced  dystrophia  adiposogenitalis,  166. 

„  ,,       „  hypopituitarism,  241. 

Thymus,  affections  of,  in  primary  lesions  of  hypophysis,  250. 

,,         lesions  of,  causing  secondary  lesions  of  hypophysis,  267. 

,,  relationship  of,  to  pituitary,  203. 

Thyroid,  affections  of,  in  primary  lesions  of  hypophysis,  250. 

,,         hypoplasia  of,  effects  of  pituitary  extracts  on,  326. 

,,         lesions  of,  causing  secondary  lesions  of  hypophysis,  262. 

„         removal  of,  effects  on  pituitary  of,  182. 

„  ,,       „         ,,      „   anterior  lobe  of,  188. 

„  „        „         „      ,,   production  of  colloid  bodies  of,  182. 

„  „        „         ,,      ,,  „  '  hyaline '  bodies  of,  182. 

„  „        „  ,,      ,,  pars  intermedia  of,  189. 

„  ,,        ,,  „      ,,  pars  nervosa  of,  189. 

Tinnitus  aurium,  in  acromegaly,  226. 
Tongue,  enlargement  of,  in  acromegaly,  226. 
Torpedo  marmorata,  44. 

,,  „  pars  anterior  of,  blood -channels  in,  44. 

Torpidity  in  acromegaly,  226. 

,,        ,,  hypopituitarism,  243. 
,,         ,,  after  experimental  operations,  140,  169. 
Tortoise,  52. 

Toxaemias  of  pregnancy,  changes  of  pituitary  in,  272. 
Tract,  optic,  involvement  of,  in  acromegaly,  226. 

„     alimentary,  effects  of  infundibulin  on,  112,  321. 
Treatment  of  pituitary  lesions,  280. 
,,  medical,  280. 

„  „        of  hypopituitarism,  280. 

„  surgical,  282. 

Trypsin,  action  of,  on  infundibulin,  101. 
'I'ii  I  a  r  cinereum,  24. 

Tubercle  bacilli,  effects  on  pituitary  of  inoculations  with,  209. 
Tumours,  artificial,  causing  direct  stimulation  of  pituitary,  171. 
„  ,,  glycosuria  caused  by,  172. 


348  THE   PITUITARY 

Typhoid  bacilli,  effects  on  pituitary  of  inoculations  with,  207. 
Type,  feminine,  in  hypopituitarism,  241. 

Ungulala,  60. 

Urinary  excretions  in  acromegaly,  229,  230. 

,,       system,  effects  of  infundibulin  on,  109,  321. 
Urotropin,  see  Hexame.thylenamine. 
Uterine  cannula,  111. 
Uterus,  effects  of  infundibulin  on,  111,  310. 

„      hour-glass  contraction  of,  after  use  of  infundibulin,  318. 

„       inertia  of,  primary,  effects  of  infundibulin  on,  312. 

,,  „         secondary,  effects  of  infundibulin  on,  314. 

,,      rupture  of,  after  use  of  infundibulin,  318. 

Vascular  supply  of  pituitary,  24. 

„  „        external,  26. 

,,  „  „        of  parahypophysis,  26. 

.,  ,,        internal,  24. 

Vision  in  acromegaly,  226. 

.,    disturbances  of,  in  primary  lesions  of  pituitary,  253 

,,     in  hypopituitarism,  243. 
Voice,  deepening  of,  in  acromegaly,  220. 
Vomiting  in  acromegaly,  226. 

,,  ,,  hypopituitarism,  243. 

Water-vascular  system  in  Ammoccetes,  41. 
Weight  of  pituitary,  14. 

„       „         „         variations  in,  according  to  age,  17. 


PRINTED  BY   WILLIAM   CLOWES  AND  SONS,   LIMITED,    LONDON   AND  BECCLES. 


Date  Due 

K-//-3X 

.7   cH 

CW   i«- 

\ 

9 

. 

RC658  B41 

cop#i 
Bell 

Pituitary. 


